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Multimodality Imaging in Cardiovascular Medicine

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Multimodality Imaging in Cardiovascular Medicine

Christopher M. Kramer, MD

Professor of Medicine and Radiology Director, Cardiovascular Imaging Center University of Virginia Health System Charlottesville, Virgina

New York

Acquisitions Editor: Richard Winters Cover Design: Joe Tenerelli Compositor: S4Carlisle Publishing Services Printer: Sheridan Press Visit our website at www.demosmedpub.com © 2011 Demos Medical Publishing, LLC. All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior written permission of the publisher. Library of Congress Cataloging-in-Publication Data â•… Multimodality imaging in cardiovascular medicine / [edited by] Christopher M. Kramer. â•…â•…â•… p.; cm. â•… Includes bibliographical references and index. â•… ISBN 978-1-933864-74-7 â•‡ 1.â•‡ Cardiovascular system—Diseases—Diagnosis—Atlases.â•… 2.â•‡ Diagnostic imaging—Atlases. I. Kramer, Christopher M. â•… [DNLM: 1. Cardiovascular Diseases—diagnosis—Atlases.â•… 2.â•‡ Diagnostic Imaging—methods—Atlases. WG 17 M961 2011] â•… RC670.M85 2011 â•… 616.1075—dc22 2010024864 Medicine is an ever-changing science. Research and clinical experience are continually expanding our knowledge, in particular our understanding of proper treatment and drug therapy. The authors, editors, and publisher have made every effort to ensure that all information in this book is in accordance with the state of knowledge at the time of production of the book. Nevertheless, the authors, editors, and publisher are not responsible for errors or omissions or for any consequences from application of the information in this book and make no warranty, express or implied, with respect to the contents of the publication. Every reader should examine carefully the package inserts accompanying each drug and should carefully check whether the dosage schedules mentioned therein or the contraindications stated by the manufacturer differ from the statements made in this book. Such examination is particularly important with drugs that are either rarely used or have been newly released on the market. Special discounts on bulk quantities of Demos Medical Publishing books are available to corporations, professional associations, pharmaceutical companies, health care organizations, and other qualifying groups. For details, please contact: Special Sales Department Demos Medical Publishing 11 W. 42nd Street, 15th Floor New York, NY 10036 Phone:â•‡ 800–532–8663 or 212–683–0072 Fax:â•… 212–941–7842 E-mail:â•… [email protected]

Made in the United States of America 10â•‡ 11â•‡ 12â•‡ 13â•‡ 14â•…â•… 5â•‡ 4â•‡ 3â•‡ 2â•‡ 1

Contents

Prefaceâ•… vii Acknowledgmentsâ•… ix Contributorsâ•… xi

1â•… Chest Pain: Typical Anginaâ•…â•… 1

Marcelo F. Di Carli

2â•…Atypical Chest Pain and Other Presentations of an

â•‡ 9â•…Multimodality Imaging in Hypertrophic Cardiomyopathyâ•…â•… 127 â•‡ Deborah H. Kwon and Milind Y. Desai

Intermediate Likelihood of Obstructive Coronary Artery Diseaseâ•…â•… 22 Aiden Abidov, Daniel S. Berman, and Rory Hachamovitch

10â•…Chronic Myocardial Ischemia

3â•… Acute ST Elevation Myocardial Infarctionâ•…â•… 45

11â•…Multimodality Imaging in Valvular Heart

Diseaseâ•…â•… 158 â•‡ Sonal Chandra, Amit R. Patel, and Lissa Sugeng

Zelmira Curillova and Scott D. Solomon

4â•…Noninvasive Imaging in Patients With Suspected

Unstable Angina or Non-ST Elevation Myocardial Infarctionâ•…â•… 58 Benjamin W. Kron and Kevin Wei

and Viabilityâ•…â•… 138 â•‡Caroline A. Daly, Otavio R. Coelho-Filho, and Raymond Y. Kwong

12â•… Aortic Dissectionâ•…â•… 192 â•‡Christopher J. François, Benjamin R. Landgraf, and Thorsten A. Bley

5â•… Post-MI Risk Stratificationâ•…â•… 71

13â•… Claudicationâ•…â•… 209

Mark R. Vesely, James A. Arrighi, Gagandeep S. Gurm, Harisha Kommana, and Vasken Dilsizian

â•‡Ali Z. Merchant, Georgeta Mihai, Anurag Sahu, and Sanjay Rajagopalan

6â•…Evaluation After Coronary Revascularizationâ•…â•… 92

14â•… Preoperative Risk Stratificationâ•…â•… 229

Joanne D. Schuijf, Ernst E. van der Wall, and Jeroen J. Bax

â•‡ Radosav Vidakovic´ and Don Poldermans

7â•…Diagnostic Tests for Clinically Suspected Acute

â•‡ Mark A. Fogel

Pulmonary Embolismâ•…â•… 103 Menno V. Huisman, Inge C. M. Mos, Albert de Roos, Lucia J. M. Kroft, and F. A. Klok

8â•…Contemporary Cardiac Imaging in Dyspnea Due to Heart Failureâ•…â•… 111 Martin St. John Sutton, Ted Plappert, and Yan Wang

15â•… Congenital Heart Diseaseâ•…â•… 238 16â•…Constrictive Pericarditis Versus Restrictive Cardiomyopathyâ•…â•… 252 â•‡ Andrew S. Flett and James C. Moon

17â•… Differential Diagnosis of Cardiomyopathiesâ•…â•… 263 â•‡Chirine Parsai, Rory O’Hanlon, and Sanjay K. Prasad

v

Contents

vi

18â•…Multimodality Imaging in Atrial

20â•… Cardiac Massesâ•…â•… 316

Arrhythmiasâ•…â•… 284 â•‡Ewa Dembowski, Joseph A. Lodato, and Amit R. Patel

â•‡ Victor A. Ferrari and Ari B. Goldberg

19â•…Noninvasive Atherosclerosis Imaging for Risk Stratificationâ•…â•… 299 â•‡ Allen J. Taylor and Patrick J. Devine

Indexâ•… 333

Preface

T

he cardiovascular imaging community has entered the era of multimodality imaging. Gone are the days when imagers identified themselves as echocardiographers or nuclear specialists, and so on. Practitioners in the field must become facile in multiple imaging modalities as each modality has its strengths and weaknesses. The different modalities now play a complementary role in the diagnostic armamentarium. New applications of echocardiography, nuclear imaging, cardiovascular magnetic resonance, and cardiac computed tomography are rapidly developing and it is imperative that trainees and practitioners alike remain up to date in the latest developments. It is becoming increasingly difficult to remain abreast of these advances in each individual modality and thus it is no longer practical to focus on one at a time. In addition, training guidelines are changing and multimodality training has become the norm. In the future, a comprehensive imaging examination is likely to help guide and certify trainees. However, before

that comes to pass, now is the time for reference texts as well as journals to move into this new era. It is in this light that we introduce this multimodality imaging atlas. We have enlisted the leading imagers in their field to contribute state-of-the-art chapters replete with outstanding multimodality imaging examples of cardiovascular pathophysiology as well as corresponding text to put the images into context at the interface with patient care. It was our aim to create a comprehensive clinically oriented atlas/text that would allow the practitioner to use as a problem-based reference to better understand which imaging modality or modalities may be of most benefit in which clinical situation. We encourage you to use the atlas in this way. We hope you benefit from reading it and using it in your practice of cardiovascular imaging as much as we did from putting it together. Christopher M. Kramer, MD

vii

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Acknowledgments

I would like to thank all of the authors for their outstanding contributions and Richard Winters for all of his help throughout the process of creating this book. Thanks also

to my family (Cathy, Alex, and Zach) for all their love and support.

ix

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Contributors

Aiden Abidov, MD, PhD Chair Department of Cardiology Sarver Heart Center Tucson, Arizona James A. Arrighi, MD Associate Professor of Medicine and Diagnostic Imaging Department of Medicine Alpert Medical School Brown University Director of Nuclear Cardiology Rhode Island Hospital Providence, Rhode Island

Zelmira Curillova, MD Instructor in Medicine Department of Medicine Boston Veterans Administration Medical Center Brigham and Women’s Hospital Harvard Medical School Boston, Massachusetts Caroline A. Daly, MB, MSc, PhD, MRCPI Department of Cardiology CREST Unit St. James’s Hospital Dublin, Ireland

Jeroen J. Bax, MD, PhD Department of Cardiology Leiden University Medical Center Leiden, The Netherlands

Ewa Dembowski, MD Cardiology Fellow Department of Medicine University of Chicago Chicago, Illinois

Daniel S. Berman, MD Director Department of Nuclear Cardiology/Cardiac Imaging Cedars-Sinai Medical Center Professor of Medicine David Geffen School of Medicine University of California, Los Angeles Los Angeles, California

Milind Y. Desai, MD Director, Cardiac CT and MR Department of Cardiovascular Medicine Heart and Vascular Institute Cleveland Clinic Cleveland, Ohio

Thorsten A. Bley, MD Assistant Professor Department of Diagnostic and Interventional Radiology University Medical Center Hamburg-Eppendorf Hamburg, Germany Sonal Chandra, MD Assistant Professor Department of Cardiology University of Chicago Medical Center Chicago, Illinois Otavio R. Coelho-Filho, MD Cardiovascular Magnetic Resonance Fellow Department of Medicine Brigham and Women’s Hospital Boston, Massachusetts

Patrick J. Devine, MD Department of Medicine Walter Reed Army Medical Center Assistant Professor of Medicine Georgetown University Washington, District of Columbia Assistant Professor of Medicine Uniformed Services University of the Health Sciences Bethesda, Maryland Marcelo F. Di Carli, MD Director of Noninvasive Cardiovascular Imaging Program Chief of Nuclear Medicine Department of Radiology and Medicine Brigham and Women’s Hospital Boston, Massachusetts

xi

xii

Vasken Dilsizian, MD Professor of Medicine and Radiology Director, Division of Nuclear Medicine Department of Diagnostic Radiology and â•… Nuclear Medicine University of Maryland School of Medicine Baltimore, Maryland Victor A. Ferrari, MD Professor of Medicine and Radiology Associate Director Noninvasive Imaging Laboratory Department of Medicine (Cardiovascular) University of Pennsylvania Philadelphia, Pennsylvania Andrew S. Flett, BSc, MRCP Heart Hospital Imaging Centre The Heart Hospital London, United Kingdom Mark A. Fogel, MD Professor of Cardiology and Radiology Director of Cardiac Magnetic Resonance The Childrens Hospital of Phildelphia Philadelphia, Pennsylvania Christopher J. François, MD Assistant Professor Department of Radiology University of Wisconsin, Madison Clinical Science Center Madison, Wisconsin Ari B. Goldberg, MD, PhD Fellow, Cardiovascular Imaging Department of Radiology University of Pennsylvania School of Medical Center Philadelphia, Pennsylvania Gagandeep S. Gurm, MD Resident Department of Diagnostic Radiology University of Maryland School of Medicine Baltimore, Maryland Rory Hachamovitch, MD, MSc Department of Cardiovascular Medicine Cleveland Clinic Cleveland, Ohio

Contributors

Menno V. Huisman, MD, PhD Department of General Internal Medicine, â•… Endocrinology Leiden University Medical Center Leiden, The Netherlands F. A. Klok MD, PhD Department of General Internal Medicine, Endocrinology Leiden University Medical Center Leiden, The Netherlands Harisha Kommana, MD Radiology Resident Department of Radiology University of Texas Medical Branch Galveston, Texas Christopher M. Kramer, MD Professor of Medicine and Radiology Director, Cardiovascular Imaging Center University of Virginia Health System Charlottesville, Virginia Lucia J. M. Kroft, MD, PhD Department of Radiology Leiden University Medical Center Leiden, The Netherlands Benjamin W. Kron, BA Research Assistant Department of Cardiovascular Division Oregon Health & Science University Portland, Oregon Deborah H. Kwon, MD Fellow Department of Cardiovascular Medicine Heart and Vascular Institute Cleveland Clinic Cleveland, Ohio Raymond Y. Kwong, MD, MPH Director of Cardiac Magnetic Resonance Imaging Department of Medicine Brigham and Women’s Hospital Boston, Massachusetts

xiii

Contributors

Benjamin R. Landgraf, BS Medical Student Department of Radiology University of Wisconsin, Madison Clinical Science Center Madison, Wisconsin Joseph A. Lodato, MD Department of Cardiology Mid-Atlantic Permanente Medical Group Largo, Maryland Ali Z. Merchant, MD Cardiology Fellow Department of Internal Medicine The Ohio State University Columbus, Ohio Georgeta Mihai, PhD Research Scientist Department of Cardiovascular Medicine Ohio State University Columbus, Ohio James C. Moon, MD, MRCP Heart Hospital Imaging Centre The Heart Hospital London, United Kingdom Inge C. M. Mos, MD Department of General Internal Medicine, Endocrinology Leiden University Medical Center Leiden, The Netherlands

Ted Plappert, CVT Echocardiography Laboratory Hospital of the University of Pennsylvania Philadelphia, Pennsylvania Don Poldermans, MD, PhD Professor of Medicine Department of Surgery Erasmus Medical Centre Rotterdam, The Netherlands Sanjay K. Prasad, MD Consultant Cardiologist Department of Cardiovascular Magnetic Resonance Royal Brompton Hospital London, England Sanjay Rajagopalan, MD Wolfe Professor of Medicine and Radiology Director, Vascular Medicine Program Department of Cardiovascular Medicine Ohio State University Medical Center Columbus, Ohio Albert de Roos, MD Professor of Radiology Department of Radiology Leiden University Medical Center Leiden, The Netherlands Anurag Sahu, MD Clinical Assistant Professor of Medicine Division of Cardiology Columbus, Ohio

Rory O’Hanlon, MD, MRCPI Consultant Cardiologist Department of Cardiology St. Vincents University Hospital Dublin, Ireland

Joanne D. Schuijf, PhD Department of Cardiology Leiden University Medical Center Leiden, The Netherlands

Chirine Parsai, MD, PhD Department of Cardiology Polyclinique les Fleurs Ollioules, France

Scott D. Solomon, MD Professor of Medicine Cardiovascular Division Brigham and Women’s Hospital Boston, Massachusetts

Amit R. Patel, MD Assistant Professor Department of Cardiology University of Chicago Medical Center Chicago, Illinois

Lissa Sugeng, MD Assistant Professor Department of Cardiology University of Chicago Medical Center Chicago, Illinois

xiv

Contributors

Martin St. John Sutton, MBBS John W. Bryfogle Professor of Cardiac Imaging University of Pennsylvania Medical Center Philadelphia, Pennsylvania

Radosav Vidakovic´, MD, PhD Department of Cardiology Clinical Hospital Center, Zemun Belgrade, Serbia

Allen J. Taylor, MD, FACC, FAHA Department of Medicine (Cardiology) Washington Hospital Center Professor of Medicine Georgetown University Washington, DC

Yan Wang, RDCS Echocardiography Laboratory Hospital of the University of Pennsylvania Philadelphia, Pennsylvania

Ernst E. van der Wall, MD, PhD Professor Department of Cardiology Leiden University Medical Center Leiden, The Netherlands Mark R. Vesely, MD Assistant Professor of Medicine Division of Cardiology University of Maryland School of Medicine Baltimore, Maryland

Kevin Wei, MD Associate Professor of Medicine Cardiovascular Division Oregon Health & Science University Portland, Oregon

Multimodality Imaging in Cardiovascular Medicine

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1

Chest Pain: Typical Angina

MA RCELO F. DI C ARLI During the last 2 decades, we have witnessed a significant improvement in the prevention and management of atherosclerotic heart disease and its devastating consequences. Despite these efforts, however, coronary artery disease (CAD) remains highly prevalent, and it represents a health care burden in industrialized and developing countries. This has resulted in a continued expansion and refinement of our noninvasive armamentarium and an intense debate regarding the strengths and weaknesses of competing imaging technologies and their appropriate clinical use. The introduction and dissemination of new technology provides the potential for expanding our diagnostic tools while also enhancing risk prediction, which is discussed throughout the book. This chapter reviews the relative contribution of noninvasive imaging modalities to diagnosis, risk prediction, and guiding management in patients with known or suspected CAD presenting with typical angina, with a focus on patients with stable chest pain syndrome.

and/or rest LV function, coronary anatomy) and what is the accuracy of the information provided. For example, Single photon emission computed tomography (SPECT), Positron emission tomography (PET), and CMR provide stress and rest perfusion information, but the latter 2 methodologies may be superior clinical tools if the imaging data improve diagnostic accuracy, better represent the actual extent of disease, and are potentially subject to less artifact. The advantage of PET over SPECT will be further enhanced, as discussed later, if it provides additional clinically relevant information not provided by SPECT, such as coronary flow reserve data. On the other hand, computed tomography angiography (CTA) represents the first means to assess anatomic CAD noninvasively, thus, a potential replacement for invasive angiography. Additionally, CTA is also a means to assess atherosclerosis, both with respect to its presence and potentially defining plaque morphology.

jâ•…N ONINVASIVE IMAGING APPROACHES

Role of Exercise Electrocardiography jâ•… CONCEPTUAL FRAMEWORK The basis for the diagnostic application of imaging tests in patients without known CAD presenting with typical angina should be viewed in light of the concept of sequential Bayesian analysis of disease probability. This analysis requires knowledge of the prevalence of the disease in the population being tested (pretest probability) as well as the sensitivity and specificity of the imaging test. In the setting of typical angina, the prevalence or pretest probability of CAD then differs on the basis of age, gender, and coronary risk factors. The presence of typical angina identifies a patient cohort with intermediate or high probability of CAD [1]. The information provided by noninvasive imaging generally falls into 1 of 3 categories, myocardial perfusion, left ventricular (LV) function, or coronary artery anatomy. The clinical utility, value, and role of a noninvasive modality are based on 2 test characteristics—what type of information is provided (eg, stress perfusion, stress

The American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA) guidelines recommend that most patients with a normal or nearly normal resting ECG who can adequately exercise undergo standard Exercise Treadmill Test (ETT) as the initial testing strategy. The guidelines further suggest that patients who are categorized as low risk by ETT be treated initially with medical therapy and those as high risk be referred for coronary angiography. The management of intermediate-risk patients is less certain. These patients will often require additional testing, either stress imaging or coronary angiography, to more accurately characterize risk [2]. This paradigm is based on certain assumptions. Patients who are classified as low risk or high risk should be accurately classified. Annual mortality rates in low-risk patients should be 1% and in high-risk patients 3%. The number of patients classified as intermediate risk should not be too large, as these patients generally will require a second test to refine risk stratification. Stress imaging (SPECT) has been shown to accurately 1

2

classify patients who are initially classified as intermediate risk by ETT [1,3]. Following this staged strategy of apply ing the low-cost ETT to the entire population and reserving more expensive SPECT imaging to refine risk stratification to patients initially classified as intermediate risk by ETT is more cost effective than applying stress or anatomic imaging as the initial test in the entire population. Cardiac CT

Coronary Artery Calcium Scoring Voluminous plaques are more prone to calcification, and stenotic lesions frequently contain large amounts of cal cium [4]. There is growing, consistent evidence that coro nary artery calcium (CAC) scores are generally predictive of a higher likelihood of ischemia (reflecting obstructive CAD), and the available data support the concept of a threshold phenomenon governing this relationship [5–10]. Indeed, the frequency of myocardial ischemia increases significantly with increasing CAC scores, especially among patients with CAC 400 [5–10] (Figure 1.1). Given the fact that CAC scores are not specific markers of obstruc tive CAD [11], however, one should be cautious in con sidering integrating this information into management decisions regarding coronary angiography, especially in patients with low-risk stress tests. Conversely, CAC scores 400, especially in symptomatic patients with intermedi ate-high likelihood of CAD as in those with typical angina, may be less effective in excluding CAD especially in young subjects and women [12]. In a recent study of symptomatic patients with intermediate likelihood of CAD, the absence

Multimodality Imaging in Cardiovascular Medicine

of CAC only afforded a negative predictive value (NPV) of 84% to exclude ischemia [10]. As discussed in the next section, CAC scores have a more important prognostic value, especially when combined with stress nuclear imaging.

Coronary CT Angiography In patients without prior revascularization, the available evidence suggests that on a per-patient basis, the average weighted sensitivity for detecting at least 1 coronary artery with 50% stenosis is 94% (range, 75%–100%), whereas the average specificity is 77% (range, 49%–100%) [13]. The corresponding average positive predictive value (PPV) and negative predictive value (NPV) are 84% (range, 50%–100%) and 87% (range, 35%–100%), respec tively, and the overall diagnostic accuracy is 89% (range, 68%–100%). Three multicenter trials (2 of them single ven dor [14,15]) evaluating the diagnostic accuracy of CTA-64 have been completed and recently published [14–16]. The results of these 3 studies confirm the robustness of CTA-64 for complete visualization of the coronary tree (Figure 1.2) and are summarized in Table 1.1. Except for the ACCURACY study, these reported accuracies of CTA to date should be interpreted in light of the relatively narrow range of CAD likelihood in patients examined (ie, high or intermediate high), as evidenced by the high prevalence of obstructive CAD in these series (56%–68%) [13,15,16]. Further, results are generally lim ited to relatively large vessel sizes (1.5 mm), excluding the results of smaller or uninterpretable vessels (generally distal vessels and side branches), the inclusion of which

F igure 1 . 1 â•… Frequency of inducible ischemia, as assessed by stress nuclear perfusion imaging, by coronary artery calcium scores, as assessed by computed tomography. These series included asymptomatic patients undergoing screening [5–7], patients undergoing clinical testing due to symptoms [9,10], or a combination [8].

C H A P T ER 1

•

Chest Pain: Typical Angina

3

F igure 1 . 2 â•… Multiplanar reformatted coronary angiographic views obtained with 64-slice multidetector computed tomography scanner. The

images show complete visualization of the coronary tree with calcified and noncalcified plaques. LAD, left anterior descending artery; LCX, proximal left circumflex artery; LM, left main artery; OM, obtuse marginal branch; RPL, right posterolateral branch; RCA, right coronary artery.

jâ•… Table 1.1â•… Diagnostic accuracy of coronary CTA in multicenter clinical trials ACCURACY [14]

CorE 64 [15]

European [16]

Weighted Average

Patients

230

291

360

881

Calcium score

No exclusions based on calcium score

,600

,600

—

CAD prevalence

25%

56%

68%

53%

Sensitivity

95%

85%

99%

93%

Specificity

83%

90%

64%

77%

PPV

64%

91%

86%

82%

NPV

99%

83%

97%

93%

CAD, coronary artery disease; CAT, computed tomography angiography; PPV, positive predictive value; NPV, negative predictive value.

lowers diagnostic accuracy. An ongoing problem with CT is that high-density objects such as calcified coronary plaques and stent struts limit its ability to accurately delin eate the degree of coronary luminal narrowing [14,17,18] (Figure 1.3). Of note, the CorE 64 [15] and the European [16] trials selected patients with calcium scores 600.

Like with invasive coronary angiography, there is emerging data supporting the notion that assessments of the extent of CAD by CTA can also provide useful prog nostic information [19–23]. A low 1-year cardiac event rate was reported for patients without obstructive CAD on Coronary computed tomography angiography (CCTA)

4

Multimodality Imaging in Cardiovascular Medicine

data suggest that the presence of noncalcified plaques (Figure 1.5) may also add prognostic information beyond the severity of underlying angiographic stenosis [24].

Evaluation of Coronary Artery Stents As mentioned earlier, the visualization of the coronary lumen within stents by CTA is more challenging than the evaluation of the native coronary arteries due to the bloom ing artifacts caused by table metal (Figure 1.6). To date, a limited number of studies assessing the value of CTA to detect in-stent restenosis have been published [25–30]. However, they all show a consistently low sensitivity to identify in-stent restenosis. The limited spatial resolution of CT [31,32], type of stent [31,32], and, especially, stent diameter (3 mm being associated with the highest num ber of partial lumen visualization and nondiagnostic scans) contribute to limited clinical results. F igure 1 . 3 â•… Multiplanar reformatted view of the right coronary artery (RCA) obtained with volumetric 320-slice multidetector computed tomography scanner. The image shows complete visualization of the RCA with a severely calcified plaque in its proximal segment leading to overestimation of underlying coronary stenosis. Follow-up invasive coronary angiography demonstrated nonobstructive plaque in this segment. Image courtesy of Dr. Frank Rybicki, Brigham and Women’s Hospital, Boston, MA.

(0.6% of 1371 patients) [23]. For patients with obstruc tive CAD, the results from 5 published reports revealed a 1-year cardiac event rate of 14.5% [23]. In the Â�largest study published to date [20], event rates were higher for patients with CCTA-defined proximal left anterior descending CAD and multivessel CAD, and survival worsened with higher CAD Prognostic Index scores (Figure 1.4). Preliminary

Evaluation of Bypass Grafts Assessing patency and progression of CAD in bypass grafts is less challenging than in the native coronary arteries, as they are generally larger and less subject to motion. Occasionally, evaluation of internal mammary grafts can be difficult due to blooming artifact from metal clips. On a per-graft basis, the average sensitivity for detecting at least 1 graft with 50% stenosis or total occlusion is 99% (range, 96%–100%), whereas the average specificity is 93% (range, 68%–100%). The corresponding average positive and NPVs are 83% (range, 37%–98%) and 99% (range, 98%–100%), respec tively, and the overall diagnostic accuracy is 97% (range, 95%–99%) [33–40]. Importantly, there is no appreciable difference in the reported diagnostic accuracies for the detec tion of stenosis or total occlusions between arterial and vein

F igure 1 . 4 â•…One-year all-cause death rates by extent and severity of Coronary computed tomography angiography (CCTA) results in 1127

patients. LAD: left anterior descending coronary artery. Reproduced with permission from Ref. 23.

C H A P T ER 1

•

Chest Pain: Typical Angina

5

F igure 1 . 5 â•… Selected multiplanar reformatted computed tomography

angiography view of the left coronary artery. There is nonobstructive Â� calcified plaque of the left main (LM) and proximal left circumflex (LCX) coronary arteries. In addition, there is a noncalcified plaque in the proximal segment of the left anterior descending artery with significant luminal narrowing (arrow).

grafts. In general, false-positive findings are related to diffi culties in evaluating distal anastomosis [39]. Despite the high degree of accuracy to detect occlusions and stenosis within grafts, CTA has limited value in the evaluation of the patient with recurrent chest pain after Coronary artery bypass graft (CABG) because this also requires an assessment of the native coronary arteries, which are more challenging because they are usually small and heavily calcified (Figure 1.6). Stress Echocardiography The hallmark of myocardial ischemia during stress echo cardiography is the induction of new regional wall motion abnormalities and reduced systolic wall thickening. This approach can be used in conjunction with exercise or dobutamine stress. The average weighted sensitivity and specificity of exercise echocardiography (15 studies, n 5 1849 patients) are 84% and 82%, respectively, which is similar to 80% and 84%, respectively, for dobutamine echocardiography (28 studies, n 5 2246 patients) [41]. The advantages of stress echocardiography include its relatively good diagnostic accuracy, widespread availability, no use of ionizing radiation, and low cost. Limitations of stress echocardiography include the challenges associated with image acquisition at peak exercise because of exer tional hyperpnoea and cardiac excursion, the fact that rapid recovery of wall motion abnormalities can be seen with mild ischemia (especially with 1-vessel disease, which limits sensi tivity), detection of residual ischemia within an infarcted ter ritory is difficult because of resting wall motion abnormality, the technique is highly operator dependent for acquisition of

F igure 1 . 6 â•…Examples of computed tomography angiography evaluation after revascularization. Panels A and B show an example of a patient with a stent in the proximal left anterior descending LAD coronary artery (arrow). Although patency of the stent is readily assessable, evaluation of Â�in-stent restenosis is more difficult due to metallic artifact leading to partial visualization of the coronary lumen. Panels C, D, E, F, and G show an example of a computed tomography angiogram in a patient after coronary artery bypass graft. Assessment of coronary artery disease progression within grafts is relatively straightforward, whereas progression of disease in the native vessels is more difficult because they are usually very small and heavily calcified. LAD, left anterior descending artery; LIMA, left internal mammary graft; OM, obtuse marginal branch; SVG, safenous vein graft; RCA, right coronary artery. Reproduced with permission from Ref. 13.

echocardiographic data and analysis of images, and the fact that good-quality complete images viewing all myocardial segments occurs in only 85% of patients. Newer techniques including second harmonic imaging and the use of intrave nous contrast agents improve image quality, but their effect on diagnostic accuracy has not been well documented. The use of IV contrast agents may also allow assessment of myo cardial perfusion [42]. However, limited data are available to establish this role for echocardiography. Like with nuclear perfusion imaging, stress echocardiog raphy is often used for risk stratification in patients with suspected or known CAD. A negative stress echocardiogram is associated with an excellent prognosis, allowing identifi cation of patients at low risk. A recent review suggests an annual hard event rate (death or myocardial infarction) of 1.2% for a normal stress echocardiogram as compared with 7.0% for an abnormal study [41,43,44]. Conversely, risk of

6

F igure 1 . 7 â•…Rates of total mortality after exercise stress echocardiography in patients with low, intermediate, and high Duke treadmill scores. Patients are further stratified by the stress echocardiography results (normal, 1-, 2-, or 3-vessels with abnormality). Data obtained from Ref. 44.

severe adverse events increases with the magnitude of abnor malities on stress echocardiography [43,44] (Figure 1.7). Stress Nuclear Imaging SPECT is the most common form of stress imaging tests. PET has advantages compared to SPECT (discussed later), but it is not widely available and thus considered an emerg ing technology in clinical practice.

Technical Considerations for PET and SPECT Several technical advantages account for the improved image quality and diagnostic ability of PET compared to SPECT including (1) routine measured (depth independent) attenuation correction, which decreases false positives and, thus, increases specificity; (2) high spatial and contrast res olution (heart-to-background ratio) that allows improved detection of small perfusion defects, thereby decreasing false negatives and increasing sensitivity; (3) high temporal resolution that allows fast dynamic imaging of tracer kinet ics, which makes absolute quantification of myocardial per fusion (in mL/min/g of tissue) possible. In addition, the use of short-lived radiopharmaceuticals allows fast, sequential assessment of regional myocardial perfusion (eg, rest and stress), thereby improving laboratory efficiency and patient throughput. Although these technical advantages have been recognized for a long time, access to PET for routine detection of CAD remains somewhat limited. Recent U.S. Food and Drug Administration approval of PET agents for imaging myocardial perfusion (ie, 82Rubidium [generator product] and 13N-ammonia [cyclotron product]) and the subsequent changes in reimbursement are responsible for much of the recent growth in clinical cardiac PET. Despite these advantages, SPECT scanners and imaging radiotrac ers (eg, 99mTc agents and 201Thallium) are still more widely available and less expensive than PET scanners and posi tron emitting radiotracers (eg, 82Rubidium, 13N-ammonia).

Multimodality Imaging in Cardiovascular Medicine

Nuclear perfusion imaging is a robust approach for diagnosing obstructive CAD, quantifying the magnitude of myocardium at risk, assessing the extent of tissue viabil ity, and guiding therapeutic management (ie, selection of patients for revascularization). The published literature with SPECT suggests that its average sensitivity for detecting 50% angiographic stenosis is 87% (range, 71%–97%), whereas the average specificity is 73% (range, 36%–100%) [45]. With the use of attenuation correction methods, the specificity improves especially among patients undergoing exercise stress testing [45]. With PET perfusion imaging, the reported average sensitivity for detecting 50% angio graphic stenosis is 91% (range, 83%–100%), whereas the average specificity is 89% (range, 73%–100%) [46]. One of the most valuable clinical applications of nuclear perfusion imaging is for risk prediction. It is well established that patients with a normal SPECT study exhibit a median rate of major adverse cardiac events of 0.6% per annum [47] (Figure 1.8). Importantly, the risk of death and myocardial infarction increases linearly with increasing magnitude of perfusion abnormalities [48,49] (Figure 1.9). As with stress echocardiography, stress imag ing results further risk stratify patients into low-risk versus higher-risk subgroups even after stratifying for preimaging results [50], a demonstration of clinical incremental prog nostic value (Figure 1.10). These findings are important in symptomatic cohorts and reflect the value of evaluating the physiology of the disease state in addition to the anatomic extent and severity of stenoses. Thus, although obstructive coronary disease may be present, normal perfusion find ings reveal that the disease is not flow limiting and that it is not prognostically significant. Despite its widespread use and clinical acceptance, a recognized limitation of this approach is that it often uncovers only coronary territories supplied by the most severe stenosis and, consequently, it is relatively insen sitive to accurately delineate the extent of obstructive angiographic CAD especially in the setting of multivessel disease [51,52]. Recent evidence suggests that 2 quan titative approaches may be able to help mitigate this limitation, at least in part. One of them relates to PET’s unique ability to assess LV function at rest and during peak stress (as opposed to poststress with SPECT) [52]. The data suggest that in normal subjects, left ventricular ejection fraction (LVEF) increases during peak vasodila tor stress [52]. In patients with obstructive CAD, how ever, the delta change in LVEF (from baseline to peak stress) is inversely related to the extent of obstructive angiographic CAD. Indeed, patients with multivessel or left main disease show a frank drop in LVEF during peak stress even in the absence of apparent perfusion defects (Figure 1.11). In contrast, those without significant CAD or with 1-vessel disease show a normal increase in LVEF (Figure 1.11). Consequently, the diagnostic sensitivity of gated PET for correctly ascertaining the presence of

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F igure 1 . 8 â•…Example of a normal myocardial perfusion single photon emission computed tomography study obtained using a 1-day 99mTc sestamibi protocol.

F igure 1 . 9 â•…Example of a severely abnormal myocardial perfusion single photon emission computed tomography study obtained using a 1-day

Tc sestamibi protocol. The images demonstrate a large and severe perfusion defect throughout the anterior, septal, and apical walls, showing complete reversibility consistent with extensive stress-induced ischemia throughout the left anterior descending coronary artery (LAD) territory. Follow-up invasive coronary angiography confirmed the presence of severe proximal LAD disease.

99m

Multimodality Imaging in Cardiovascular Medicine

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F igure 1 . 1 0 â•…Rates of cardiac death and myocardial

infarction over a 19-month follow-up in patients without prior coronary artery disease undergoing stress single photon emission computed tomography ( SPECT). Patients are separated into low, intermediate, and high Duke treadmill scores. Patients are further stratified by the stress SPECT results (normal, mild, and moderately to severe abnormal scans). Significant difference in event rates across scan categories (P , .01) is present in the intermediate and high Duke treadmill score subgroups as a function of scan result. Reproduced with permission from Ref. 50.

F igure 1 . 1 1 â•… Gated rest-stress

Rubidium myocardial perfusion positron emission tomography (PET) images illustrating the added value of left ventricular function over the perfusion information. Panel A (left) demonstrates a normal rise in left ventricular ejection fraction (LVEF) from rest to peak stress (bottom) in a patient with angiographic single-vessel coronary artery disease (CAD), showing a single perfusion defect in the inferior wall on the PET images (arrows). Panel B (right) demonstrates an abnormal drop in left ventricular ejection fraction (LVEF) from rest to peak stress in a patient with angiographic multivessel vessel CAD, also showing a single perfusion defect in the inferolateral wall on the PET images (arrows). Reproduced with permission from Ref. 13. 82

multivessel disease increases from 50% to 79% [52]. A recent study suggests that measurements of so-called LVEF reserve also have prognostic implications [53] (Figure 1.12). The second approach is based on the ability of PET to enable absolute measurements of myocardial blood flow (in mL/min/g) and coronary vasodilator reserve [54–57]. In patients with so-called balanced ischemia or diffuse CAD, measurements of coronary vasodila tor reserve would uncover areas of myocardium at risk that would generally be missed by performing

only relative assessments of myocardial perfusion [58] (Figure 1.13). These estimates of coronary vasodilator reserve appear to contribute to risk prediction, which would be Â�especially in patients with normal perfusion [59] (Figure 1.14). It is important to point out, however, that neither of these approaches has been tested in pro spective clinical trials. Another limitation of the myocardial perfusion Â�imaging approach is that it fails to describe the presence and extent of subclinical atherosclerosis [60,61]. This is not unexpected since the myocardial perfusion imaging

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F igure 1 . 1 2 â•…Annualized rates of cardiac events (cardiac death

and nonfatal myocardial infarction) and all-cause death were lower in patients with left ventricular ejection fraction (LVEF) reserve 0% compared to those with LVEF reserve ,0%. *P , .001 for cardiac events and all-cause death. Reproduced with permission from Ref. 53.

F igure 1 . 1 3 â•… The top panel shows a stress-rest 82Rubidium positron emission tomography scan demonstrating a large and severe perfusion defect throughout the inferior and inferolateral left ventricular walls, which was fixed. The lower panel demonstrates the results of the quantitative analysis using the approach developed at Brigham and Women’s Hospital, Boston, MA. The data demonstrate severely impaired Â�dipyridamole-stimulated myocardial blood flow (MBF) resulting in a markedly reduced coronary flow reserve (CFR). Coronary angiography demonstrated total occlusion of the right and left circumflex coronary arteries and a severe stenosis in the mid-left anterior descending artery. LAD, left anterior descending coronary artery; LCX, proximal left circumflex coronary artery; RCA, right coronary artery MACE, major adverse cardiac events. Reproduced from Ref. 46, with permission from the Society of Nuclear Medicine.

F igure 1 . 1 4 â•… Unadjusted Kaplan-Meier survival curves showing value of coronary flow reserve (CFR), as assessed by 13N-ammonia positron emission tomography in predicting outcome up to 3 years. Reproduced with permission from Ref. 59.

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method is designed and targeted on the Â�identification of flow-limiting stenoses. This is potentially important Â�especially in patient subgroups with intermediate-high clinical risk in whom there may be extensive Â�subclinical CAD and may explain, at least in part, the limitations of perfusion imaging alone to identify low-risk patients among those with high clinical risk (eg, diabetes, Â�end-stage renal disease) [47].

Dual-Modality CT and Nuclear Perfusion Imaging The potential to acquire and quantify rest and stress myo cardial perfusion and noncontrast CT scan for CAC scor ing from a single dual-modality study may offer a unique opportunity to expand the prognostic value of stress nuclear imaging. The rationale for this integrated approach is predicated on the fact that the perfusion imaging approach is designed to uncover only obstructive atherosclero sis and, thus, insensitive for detecting subclinical disease (Figure 1.15) [62]. The CAC score, reflecting the anatomic extent of atherosclerosis [63], may offer an opportunity to

Multimodality Imaging in Cardiovascular Medicine

improve the conventional models for risk assessment using nuclear imaging alone (especially in patients with normal perfusion), a finding that may serve as a more rational basis for personalizing the intensity and goals of medical therapy in a more cost-effective manner. For example, recent data suggest that quantification of CAC scores at the time of stress nuclear imaging using a dual-modality approach can enhance risk predictions in patients with suspected CAD [10]. In a consecutive series of 621 patients without prior CAD undergoing stress PET imaging and CAC scoring in the same clinical setting, risk-adjusted analysis demon strated that for any degree of perfusion abnormality, there was a stepwise increase in adverse events (death and myo cardial infarction) with increasing CAC scores. This find ing was observed in patients with and without evidence of ischemia on PET MPI. The annualized event rate in patients with normal PET MPI and no CAC was substantially lower than that among those with normal PET MPI and a CAC 1000 (Figure 1.16). Likewise, the annualized event rate in patients with ischemia on PET MPI and no CAC was lower than that among those with ischemia and a CAC 1000.

F igure 1 . 1 5 â•…Illustration of the complementary role of nuclear perfusion imaging and computed tomography calcium scoring using integrated hybrid imaging. The top panel shows the stress-rest myocardial perfusion positron emission tomography (PET) scan of a patient with atypical chest pain. This patient had a calcium score of zero. The lower panel shows the stress-rest myocardial perfusion PET scan of a similar patient with atypical chest pain and dyspnea. By contrast, this patient had extensive atherosclerosis with a calcium score of 1130. The 2 examples show that flow-limiting disease was excluded in both patients; the 2 differed in the extent of underlying atherosclerosis, which may indicate different clinical risk. SA, short axis; VLA, vertical long axis; HLA, horizontal long axis. Reproduced from Ref. 62.

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CAD, which as discussed earlier is one of the pitfalls of stress perfusion scintigraphy (Figure 1.17). Although CT coronary angiography as an adjunct to perfusion imaging could expand the opportunities to identify patients with noncalcified plaques at greater risk of adverse cardio vascular events, it is unclear how much added prognos tic information there is in the contrast CT scan over the simple CAC scan [67]. Stress Cardiac Magnetic Resonance Imaging

F igure 1 . 1 6 â•…Adjusted survival curves for freedom from death or myocardial infarction (MI) adjusted for age, sex, symptoms, and conventional coronary artery disease risk factors in patients without ischemia (A) and with ischemia (B). CAC, coronary artery Â�calcium. Reproduced from Ref. 10.

As discussed here, CTA provides excellent diagnostic sensitivity for stenoses in the proximal and mid segments (1.5 mm in diameter) of the main coronary arteries. This limitation is unlikely to change because a significant improvement in spatial resolution for CT will have to be coupled with a substantial increase in radiation dose in order to maintain noise and image quality constant. However, this limitation of CT can be offset by the MPI information that is generally not affected by the location of coronary stenoses. First clinical results appear encour aging, and they support the notion that dual-modality imaging may offer superior diagnostic information with regard to identification of the culprit vessel [64–66]. For example, Rispler et al reported a significant improvement in specificity (63%–95%) and PPV (31%–77%) without a change in sensitivity or NPV for detection of obstruc tive CAD as defined by quantitative coronary angiogra phy in a cohort of 56 patients with known or suspected CAD undergoing hybrid SPECT/CTA imaging [66]. On the other hand, CTA improves the detection of multivessel

The 2 approaches used with CMR to evaluate known or suspected CAD include the assessment of regional myo cardial perfusion or wall motion, the latter being anal ogous to dobutamine echocardiography. The logistics for stress MRI studies require the use of pharmacologic stress agents including vasodilators and dobutamine. Myocardial perfusion is evaluated by injecting a bolus of contrast agent followed by continuous data acquisition as the contrast passes through the cardiac chambers and into the myocardium. Relative perfusion deficits are rec ognized as regions of low signal intensity (black) within the myocardium (Figure 1.18). In addition, delayed imaging allows detection of bright areas of myocardial scar (white), which further enhances the utility of this approach for diagnosis of CAD (so-called delayed gado linium enhancement) (Figure 1.18). The major advantage of dobutamine-CMR over dobu tamine echocardiography is better image quality and sharper definition of endocardial borders against blood pool. Consequently, dobutamine-CMR appears to have higher diagnostic accuracy than dobutamine echocardiog raphy for detection of CAD [68], especially in patients with poor acoustic window [69]. A limitation of high-dose dobutamine stress CMR is that it bears the potential risk of severe side effects, such as hypotension, and severe ven tricular arrhythmias in the inhospitable environment of the MR scanner. The advantage of stress perfusion CMR over SPECT is its clearly higher spatial resolution allowing detection of Â�subendocardial defects that may be missed by SPECT [70]. The major limitation of perfusion CMR is the common Â�presence of so-called dark-rim artifacts, which may cause false-positive readings. The addition of the delayed enhancement information in a stepwise interpreta tion algorithm has been proposed as a way to avoid falsepositive readings [71]. Although this approach may clearly help in patients with prior CAD, its impact in patients with suspected CAD may be more limited. Additionally, quan tification of the severity of stress-induced peri-infarct isch emia is more challenging than that with nuclear techniques (Figure 1.19). In a recent review of the published literature [72], stress-induced wall motion abnormalities imaging dem onstrated a sensitivity of 83% and specificity of 86% on a patient level. Stress myocardial perfusion imaging

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F igure 1 . 1 7 â•… Three-dimensional volumerendered myocardial perfusion positron emission tomography images obtained with 82 Rubidium with overlaying coronary computed tomography angiographic images (top panel), and corresponding invasive coronary angiographic views (lower panel) of a 65-yearold diabetic patient presenting with atypical chest pain. The perfusion images demonstrate moderate perfusion defects in the anterior and inferolateral walls, corresponding to stenosis in the left anterior descending and proximal left circumflex (LCX) coronary arteries (arrows). This image fusion display allows detection of culprit coronary stenosis and can be helpful in guiding targeted interventions. RCA, right coronary artery.

F igure 1 . 1 8 â•…Example of stress, rest, and

delayed CMR images in a diabetic middle-aged man with exertional dyspnea who has LVH and normal LVF with a small area of inferior hypokinesis. Images represent short-axis views of the left ventricle in basal (left) and apical (right) planes. The stress images demonstrate extensive, concentric areas of subendocardial hypoperfusion (arrows). The rest images demonstrate only a small subendocardial perfusion deficit in the inferior and inferoseptal walls, matching the area of gadolinium enhancement on the delayed images. This study is consistent with extensive 3-vessel territory ischemia with a relatively small area of subendocardial scar in the right coronary territory. The patient was found to have severe 3-Â�vessel coronary artery disease on invasive coronary angiography. Images are courtesy of Dr. Raymond Kwong, Brigham and Women’s Hospital, Boston, MA. CMR, cardiac magnetic resonance; LVH, left ventricular hypertrophy; LVF, left ventricular function.

Multimodality Imaging in Cardiovascular Medicine

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F igure 1 . 1 9 â•…Example of stress, rest, and delayed cardiac magnetic resonance (CMR) images in a man with known coronary artery disease prior myocardial infarction (MI), and stenting of the left anterior descending coronary artery (LAD). Images represent mid short-axis views of the left ventricle. The stress images demonstrate extensive anterior, anterolateral, and septal subendocardial hypoperfusion (arrows). The rest images demonstrate residual areas of subendocardial perfusion deficit in the anterolateral and septal walls, matching the area of gadolinium enhancement on the delayed images. This study is consistent with a large area of prior MI throughout the LAD territory with evidence of some residual stress-induced peri-infarct ischemia. However, quantification of the magnitude of residual ischemia is more challenging owing to the presence of prior MI in the same territory. Image courtesy of Dr. Raymond Kwong, Brigham and Women’s Hospital, Boston, MA.

demonstrated a sensitivity of 91% and specificity of 81% on a patient level. As with the CT literature, the summary sensitivities and specificities for perfusion imaging and stress-induced wall motion abnormalities imaging in this meta-analysis were obtained in patients with a high prev alence of CAD (prior MI) selected to undergo coronary angiography Â�(disease prevalence was 71% for the stress perfusion studies and 57% for the wall motion studies). Limited data in patients without prior CAD (especially without prior MI) suggest that diagnostic accuracy of the myocardial Â�perfusion approach may be more modest [71]. The combination of wall motion and myocardial perfusion analysis in response to dobutamine stress improves sensi tivity for the diagnosis of CAD but does not enhance over all diagnostic accuracy because of a concomitant decrease in specificity [73]. There is growing, consistent evidence that ischemia measurements derived from stress CMR studies also have prognostic significance [74]. In line with the nuclear and echocardiography literature, a normal CMR study is asso ciated with a good prognosis [69,74–79]. Conversely, the presence of new wall motion abnormalities [69,75,79], regional perfusion defects [77], the combination of wall motion abnormalities and perfusion defects [76,78], and the presence of late gadolinium enhancement [77,78,80] were all predictors of adverse events.

jâ•…S ELECTING A TESTING STRATEGY IN PATIENTS WITH OUT KNOWN CAD As discussed above, there are many options for the evalua tion of a patient with suspected CAD presenting with typical angina symptoms. The critical questions to be answered by a testing strategy include the following: (1) Does the presence of typical angina reflect obstructive CAD? (2) What is the short- and long-term risk? (3) Does the patient need to be considered for revascularization? The ACC/AHA guidelines recommend that most patients with a normal or nearly normal resting ECG who can adequately exercise undergo a standard ETT as the initial testing strategy. The guidelines further suggest that patients who are categorized as low risk by ETT be treated initially with medical therapy and those who are high risk be referred for coronary angiography. The management of intermediate-risk patients is less certain. These patients will often require additional testing, either stress imaging or coronary angiography, to more accurately character ize risk [2]. One potential caveat with this approach is that the number of patients classified as intermediate risk should not be too large, as these patients generally will require a second test to refine risk stratification. This con cept may be especially important for patients with typical angina, who by definition are an intermediate-high risk

Multimodality Imaging in Cardiovascular Medicine

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Low-Intermediate (<50%)

Intermediate-High (>50%)

ETT

Low risk

High (>90%)

Stress imaging

Int-high risk Low-int risk

Medical therapy

High risk

Cath/revascularization

F igure 1 . 2 0 â•… Possible testing strategy for patients with suspected coronary artery disease (CAD) presenting with typical angina. Strategy is based on established guidelines as well as consideration of added clinical and economic outcomes of each procedure for each patient subset. ETT, Exercise Treadmill Test.

cohort. Stress imaging with either SPECT or echocardiog raphy has been shown to accurately classify patients who are initially classified as intermediate risk by ETT [1,3] (Figures 1.7, 1.10, and 1.20). Following this staged strat egy of applying the low-cost ETT to the entire popula tion and reserving more expensive imaging to refine risk stratification for patients initially classified as interme diate risk by ETT is more cost effective than applying stress or anatomic imaging as the initial test in the entire population. An imaging strategy is the recommended first step for patients who are unable to exercise and/or those with abnormal resting ECGs [45,81]. Importantly, the most recent documents regarding appropriate use of radionuclide and echocardiography imaging also con sidered that imaging may be an appropriate first step in patients with intermediate-high likelihood of CAD, as for example, those presenting with typical angina [82,83] (Figure 1.21). In considering the potential clinical appli cation of imaging modalities, the evidence supporting the role of assessment of ischemia versus anatomy must be considered. From the discussion here, a normal CTA is helpful as it effectively excludes the presence of obstruc tive CAD and the need for further testing, defines a low clinical risk, and makes management decisions straight forward. Because of its limited accuracy to define stenosis

severity [84,85] and predict flow-limiting disease [86], however, abnormal CTA results are more problematic to interpret and to use as the basis for defining the poten tial need of invasive coronary angiography and revascu larization. Consequently, CTA may be an effective first imaging strategy if the number of abnormal scans is not excessively large (eg, younger patients, low-intermediate CAD likelihood) (Figure 1.21), as those patients will require a second test for defining subsequent manage ment. Patients with typical angina are by definition more likely to have obstructive CAD, which may render the CTA-first approach less effective. The justification of stress imaging in testing Â�strategies has hinged on the identification of patients who may benefit from a revascularization strategy by means of noninvasive estimates of jeopardized myocardium rather than angiography-derived anatomy. The advantages of this approach include avoidance of excess catheteriza tions with their associated cost and risk and the potential oculostenotic reflex [87] and identification of patients with extensive ischemia [88] as a means to identify revascularization candidates (Figure 1.22). The value of ischemia information for optimizing clinical deci sion making has been demonstrated by multiple stud ies. Revascularization in patients with 3-vessel CAD was associated with enhanced survival only in those patients

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F igure 1 . 2 1 â•…Alternative optimized testing strategy for patients with suspected coronary artery disease (CAD) presenting with typical angina.

Strategy is based on established guidelines as well as consideration of added clinical and economic outcomes of each procedure for each patient subset. CTA, computed tomography angiography.

F igure 1 . 2 2 â•… Natural log of the hazard function (based on Cox proportional hazards model) versus percent of the myocardium ischemic on stress single photon emission computed tomography. Separate lines depicting the relationship between risk and ischemia are shown for patients treated with medical therapy (Medical Rx) and revascularization (Revasc). Significant difference across ischemia for risk and between treatment groups (interaction from

multivariable model P , .01). Reproduced from Ref. 87.

with ischemic ETT results, whereas medical therapy was a superior initial therapy in patients without this finding [89]. Similar findings were reported in the COURAGE nuclear Â�substudy [90] and in risk-adjusted analysis of large registries [87]. The benefit of an ischemia-guided

approach to management is further supported by inva sive estimates of flow-limiting stenosis (eg, fractional flow reserve, FFR) [91]. In the setting of an FFR 0.75, revascularization can be safely deferred without increased patient risk, despite the Â�presence of what visually appears

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to be a significant stenosis [91]. Indeed, cardiac event rates are extremely low in these patients; even lower than predicted if treated with PCI [92], and this differential risk appears to be sustainable long term [93]. This is further supported by a recent report from a ran domized clinical trial evaluating the efficacy of revascular ization decisions using an angiographically guided versus a functionally guided (as assessed by FFR) percutaneous coro nary intervention (PCI) in patients with multivessel CAD [94]. In this study, routine use of an FFR-guided approach signifi cantly reduced the rate of the composite endpoint of death, nonfatal myocardial infarction, and repeat revascularization by 28% at 1 year compared to the angiographically guided strategy. In addition, both groups have high and comparable rates of angina-free patients at 1 year [94]. Furthermore, in patients with visually defined left main coronary disease, an FFR 0.75 was associated with excellent 3-year Â�survival and freedom from major adverse cardiovascular events [92]. Conversely, event rates are increased when lesions with FFR 0.75 are not revascularized [95]. The acceptable diagnostic accuracy of stress imaging approaches, along with their robust risk stratification, and the ability of ischemia information to identify patients who would benefit from revascularization suggest a potential role as a first imaging strategy in patients with intermediatehigh likelihood of CAD or as a follow-up to abnormal CTA findings (Figure 1.21). Although the available data suggest similar diagnostic accuracy for SPECT, PET, echo cardiography, and CMR, the choice of strategy depends on availability and local expertise. Special Groups Women.â•… The use of exercise testing in women presents dif ficulties that are not experienced in men. These difficulties reflect the differences between men and women regarding the prevalence of CAD and the sensitivity and specific ity of exercise testing. Although obstructive CAD is one of the principal causes of death in women, the prevalence (and thus the pretest probability) of this disease is lower in women than it is in men of comparable age, especially in premenopausal women. Compared with men, the lower pretest probability of disease in women means that more test results are false positive. For example, almost half the women with angina symptoms in the CASS study, many of whom had positive exercise test results, had normal coro nary arteriograms. Exercise testing is less sensitive in women than it is in men, and some studies have found it also to be less spe cific [1,96,97]. Indeed, ECG changes during exercise have been reported to be of diminished accuracy in women as a result of more frequent resting ST-T-wave changes, lower ECG voltage, and hormonal factors such as endog enous estrogen in premenopausal women and hormone replacement therapy in postmenopausal women [97]. The

Multimodality Imaging in Cardiovascular Medicine

inability of many women to exercise to maximum aerobic capacity, the greater prevalence of mitral valve prolapse and syndrome X in women, and differences in microvas cular function (leading perhaps to coronary spasm) are other reasons that may help explain the differences with men. The difficulties of using exercise testing for diagnos ing obstructive CAD in women have led to speculation that stress imaging may be preferred over standard stress testing [97]. Although the optimal strategy for diagnos ing obstructive CAD in women remains to be defined, the current recommendations suggest that there are currently insufficient data to justify replacing standard exercise testing with stress imaging when evaluating symptomatic women for CAD [1,96,97]. Elderly.â•… ACC/AHA guidelines recommend that the stan dard ETT be used as the initial stress testing modality in patients without prior revascularization who can ade quately exercise and who have a normal or near normal resting ECG [81,96,98]. The guidelines acknowledge that published data on stress testing in the elderly are limited but do not recommend altering this recommendation simply on the basis of age. Factors influencing the utility of stan dard ETT include the fact that functional capacity often is compromised from muscle weakness and deconditioning, making the decision about an exercise test versus a phar macologic stress test more important. Elderly patients are more likely to hold the handrails tightly, thus reducing the validity of treadmill time for estimating metabolic equiv alents (METs). Arrhythmias occur more frequently with increasing age, especially at higher workloads. According to the guidelines, many elderly patients will be candidates for stress imaging, either due to resting ECG abnormali ties or inability to exercise. Even in those elderly patients who are candidates for standard ETT, however, the limited published data suggest that a large percentage (one-half to two-thirds) will be classified as intermediate risk [99], which will often necessitate performing another test. Furthermore, the subset classified as low risk may not be correctly classified (annual mortality rate is not 1%). Due to the fact that coronary calcification increases with age and that coronary CTA has limited diagnostic accu racy in the setting of dense calcifications limited value, stress imaging may be considered as the initial stress test modality in the elderly. Diabetes and Renal Dysfunction.â•… Certain subsets of patients appear to benefit significantly from stress imaging. Diabetics with an abnormal perfusion scan or an abnor mal stress echo have a higher subsequent event rate than nondiabetic patients with the same extent or severity of abnormality [100–102]. Similarly, patients with chronic renal disease can be well risk stratified by either stress per fusion imaging or stress echocardiography in the absence

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of symptoms of CAD [103–105]. Accelerated CAD is a fre quent complication of renal disease, and use of noninvasive imaging for prognostication avoids the risk of administer ing contrast, necessary with CT angiography or coronary angiography.

jâ•…S ELECTING A STRATEGY IN PATIENTS WITH KNOWN CAD Use and selection of testing strategies in patients with typical angina and established CAD (ie, prior angiogra phy, prior MI, prior revascularization) differ from those without prior CAD [81,96,98]. Although standard ETT may help distinguish cardiac from noncardiac chest pain, exercise ECG has a number of limitations following MI and revascularization (especially CABG). These patients frequently have rest ECG abnormalities. In addition, there is a clinical need to document both the magnitude and site of ischemia. Consequently, imaging tests are preferred for evaluating patients in this group. There are also important differences in the effec tiveness of imaging tests in these patients. As discussed above, coronary CTA is limited in patients with prior

revascularization. Patients who have previously undergone CABG are a particularly heterogeneous group with respect to the Â�anatomic basis of ischemia and its implications for subsequent morbidity and mortality. In addition to graft attrition, progression of native CAD is not uncommon in symptomatic patients. Although bypass grafts are good tar gets for CTA, the native circulation is not [13]. Likewise, blooming artifacts from metallic stents also limit the appli cation of CTA in patients with prior PCI [13]. Although newer stent material may change the potential role of CTA in the future, it is probably not the first line of testing in these patients. If an anatomic strategy is indicated, direct referral to invasive angiography is recommended [106]. Stress imaging approaches are especially useful and preferred in symptomatic patients with established CAD (Figure 1.23). As in patients without prior CAD, normal imaging studies in symptomatic patients with established CAD also identify a low-risk cohort. In those with abnor mal stress imaging studies, the degree of abnormality relates to post-test risk [1,98]. In addition, stress imaging approaches can localize and quantify the magnitude of isch emia (especially with perfusion imaging), thereby assisting in planning targeted revascularization procedures. Like in patients without prior CAD, the choice of stress imaging strategy depends on availability and local expertise.

Typical Angina

ETT (?)

Low risk

Stress imaging

Int-high risk

Low-int risk

Medical therapy

High risk

Cath/revascularization

F igure 1 . 2 3 â•… Possible testing strategy for patients with known coronary artery disease (CAD) presenting with typical angina. Strategy is based

on established guidelines as well as consideration of added clinical and economic outcomes of each procedure for each patient subset. ETT, Exercise Treadmill Test.

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jâ•… CONCLUSIONS Innovation in noninvasive cardiovascular imaging is rap idly advancing our ability to image in great detail the structure and function in the heart and vasculature. This innovation in imaging promises to provide new insights into pathophysiology of disease, earlier detection of dis ease, and quantitative methods to evaluate response to therapeutic interventions. Multiple imaging modalities targeting various aspects of cardiac and vascular anatomy and/or function are avail able, and each provide potentially useful information in the evaluation of patients with typical angina. To date, there is limited data on head-to-head comparisons between imag ing modalities, and there is considerable controversy on the relative value of imaging technologies. Consequently, selec tion of the best test for an individual patient remains an art that should focus on risk stratification and prediction of which patients may benefit from revascularization. The goals of future investigation will be to refine these technolo gies, address the issue of cost-effectiveness, and validate a range of clinical applications in large-scale clinical trials.

â•‡â•‡ 9.

â•‡ 10.

â•‡ 11.

â•‡ 12.

â•‡ 13.

â•‡ 14.

â•‡ 15.

jâ•… REFERENCES â•‡â•‡ 1. Gibbons RJ, Chatterjee K, Daley J, et al. ACC/AHA/ACP-ASIM guidelines for the management of patients with chronic stable angina: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Patients with Chronic Stable Angina). J Am Coll Cardiol. 1999;33(7):2092–2197. â•‡â•‡ 2. Gibbons RJ, Balady GJ, Bricker JT, et al. ACC/AHA 2002 guideline update for exercise testing: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1997 Exercise Testing Guidelines). Circulation. October 1, 2002;106(14):1883–1892. â•‡â•‡ 3. Berman DS, Hachamovitch R, Kiat H, et al. Incremental value of prognostic testing in patients with known or suspected ischemic heart disease: a basis for optimal utilization of exercise technetium-99m sestamibi myocardial perfusion single-photon emission computed tomography [published erratum appears in J Am Coll Cardiol 1996 March 1;27(3):756]. J Am Coll Cardiol. 1995;26(3):639–647. â•‡â•‡ 4. Wexler L, Brundage B, Crouse J, et al. Coronary artery calcifi cation: pathophysiology, epidemiology, imaging methods, and clinical implications: a statement for health professionals from the American Heart Association. Writing Group. Circulation. September 1, 1996;94(5):1175–1192. â•‡â•‡ 5. He ZX, Hedrick TD, Pratt CM, et al. Severity of coronary artery calcification by electron beam computed tomography predicts silent myocardial ischemia. Circulation. 2000;101:244–251. â•‡â•‡ 6. Berman DS, Wong ND, Gransar H, et al. Relationship between stress-induced myocardial ischemia and atherosclerosis mea sured by coronary calcium tomography. J Am Coll Cardiol. 2004;44:923–930. â•‡â•‡ 7. Anand DV, Lim E, Raval U, Lipkin D, Lahiri A. Prevalence of silent myocardial ischemia in asymptomatic individuals with subclini cal atherosclerosis detected by electron beam tomography. J Nucl Cardiol. July–August 2004;11(4):450–457. â•‡â•‡ 8. Ramakrishna G, Miller TD, Breen JF, Araoz PA, Hodge DO, Gibbons RJ. Relationship and prognostic value of coronary artery calcification by electron beam computed tomography to

â•‡ 16.

â•‡ 17.

â•‡ 18.

â•‡ 19.

â•‡ 20.

â•‡ 21.

â•‡ 22.

â•‡ 23. â•‡ 24.

â•‡ 25.

stress-induced ischemia by single photon emission computed tomography. Am Heart J. May 2007;153(5):807–814. Schepis T, Gaemperli O, Koepfli P, et al. Added value of coronary artery calcium score as an adjunct to gated SPECT for the evalua tion of coronary artery disease in an intermediate-risk population. J Nucl Med. September 2007;48(9):1424–1430. Schenker MP, Dorbala S, Hong EC, et al. Interrelation of coro nary calcification, myocardial ischemia, and outcomes in patients with intermediate likelihood of coronary artery disease: a com bined positron emission tomography/computed tomography study. Circulation. April 1, 2008;117(13):1693–1700. Nallamothu BK, Saint S, Bielak LF, et al. Electron-beam computed tomography in the diagnosis of coronary artery disease: a metaanalysis. Arch Intern Med. March 26, 2001;161(6):833–838. Knez A, Becker A, Leber A, et al. Relation of coronary calcium scores by electron beam tomography to obstructive disease in 2115 symp tomatic patients. Am J Cardiol. May 1, 2004;93(9):1150–1152. Di Carli MF, Hachamovitch R. New technology for noninvasive evaluation of coronary artery disease. Circulation. March 20, 2007;115(11):1464–1480. Budoff MJ, Dowe D, Jollis JG, et al. Diagnostic performance of 64-multidetector row coronary computed tomographic angiogra phy for evaluation of coronary artery stenosis in individuals with out known coronary artery disease: results from the prospective multicenter ACCURACY (Assessment by Coronary Computed Tomographic Angiography of Individuals Undergoing Invasive Coronary Angiography) trial. J Am Coll Cardiol. November 18, 2008;52(21):1724–1732. Miller JM, Rochitte CE, Dewey M, et al. Diagnostic performance of coronary angiography by 64-row CT. N Engl J Med. November 27, 2008;359(22):2324–2336. Meijboom WB, Meijs MF, Schuijf JD, et al. Diagnostic accuracy of 64-slice computed tomography coronary angiography: a prospec tive, multicenter, multivendor study. J Am Coll Cardiol. December 16, 2008;52(25):2135–2144. Hoffmann U, Moselewski F, Cury RC, et al. Predictive value of 16-slice multidetector spiral computed tomography to detect sig nificant obstructive coronary artery disease in patients at high risk for coronary artery disease: patient-versus segment-based analysis. Circulation. October 26, 2004;110(17):2638–2643. Mollet NR, Cademartiri F, Krestin GP, et al. Improved diagnostic accuracy with 16-row multi-slice computed tomography coronary angiography. J Am Coll Cardiol. January 4, 2005;45(1):128–132. Pundziute G, Schuijf JD, Jukema JW, et al. Prognostic value of multi-slice computed tomography coronary angiography in patients with known or suspected CAD. J Am Coll Cardiol. 2007;49:62–70. Min JK, Shaw LJ, Devereux RB, et al. Prognostic value of multi detector coronary computed tomographic angiography for pre diction of all-cause mortality. J Am Coll Cardiol. September 18, 2007;50(12):1161–1170. Gilard M, Le Gal G, Cornily JC, et al. Midterm prognosis of patients with suspected coronary artery disease and nor mal multislice computed tomographic findings: a prospective management outcome study. Arch Intern Med. August 13–27, 2007;167(15):1686–1689. Matsumoto N,SatoY,Yoda S,et al.Prognostic value of non-obstructive CT low-dense coronary artery plaques detected by multislice com puted tomography. Circ J. December 2007;71(12):1898–1903. Shaw LJ, Narula J. Risk assessment and predictive value of coronary artery disease testing. J Nucl Med. August 2009;50(8): 1296–1306. van Werkhoven JM, Schuijf JD, Gaemperli O, et al. Incremental prognostic value of multi-slice computed tomography coronary angiography over coronary artery calcium scoring in patients with suspected coronary artery disease. Eur Heart J. November 2009;30(21):2622–2629. Cademartiri F, Mollet N, Lemos PA, et al. Usefulness of multislice computed tomographic coronary angiography to assess in-stent restenosis. Am J Cardiol. September 15, 2005;96(6):799–802.

C H A P T ER 1

•

Chest Pain: Typical Angina

â•‡ 26. Gaspar T, Halon DA, Lewis BS, et al. Diagnosis of coronary in-stent restenosis with multidetector row spiral computed tomography. J Am Coll Cardiol. October 18, 2005;46(8):1573–1579. â•‡ 27. Gilard M, Cornily JC, Pennec PY, et al. Assessment of coronary artery stents by 16-slice computed tomography. Heart. January 2006;92(1):58–61. â•‡ 28. Gilard M, Cornily JC, Rioufol G, et al. Noninvasive assessment of left main coronary stent patency with 16-slice computed tomogra phy. Am J Cardiol. January 1, 2005;95(1):110–112. â•‡ 29. Kitagawa T, Fujii T, Tomohiro Y, et al. Noninvasive assessment of coronary stents in patients by 16-slice computed tomography. Int J Cardiol. May 10, 2006;109(2):188–194. â•‡ 30. Schuijf JD, Bax JJ, Jukema JW, et al. Feasibility of assessment of coronary stent patency using 16-slice computed tomography. Am J Cardiol. August 15, 2004;94(4):427–430. â•‡ 31. Mahnken AH, Muhlenbruch G, Seyfarth T, et al. 64-Slice computed tomography assessment of coronary artery stents: a phantom study. Acta Radiol. February 2006;47(1):36–42. â•‡ 32. Maintz D, Seifarth H, Raupach R, et al. 64-Slice multidetector coro nary CT angiography: in vitro evaluation of 68 different stents. Eur Radiol. April 2006;16(4):818–826. â•‡ 33. Anders K, Baum U, Schmid M, et al. Coronary artery bypass graft (CABG) patency: assessment with high-resolution submillimeter 16-slice multidetector-row computed tomography (MDCT) versus coronary angiography. Eur J Radiol. March 2006;57(3):336–344. â•‡ 34. Chiurlia E, Menozzi M, Ratti C, Romagnoli R, Modena MG. Follow-up of coronary artery bypass graft patency by mul tislice computed tomography. Am J Cardiol. May 1, 2005;95(9): 1094–1097. â•‡ 35. Malagutti P, Nieman K, Meijboom WB, et al. Use of 64-slice CT in symptomatic patients after coronary bypass surgery: evaluation of grafts and coronary arteries. Eur Heart J. July 17, 2006. â•‡ 36. Martuscelli E, Romagnoli A, D’Eliseo A, et al. Evaluation of venous and arterial conduit patency by 16-slice spiral computed tomogra phy. Circulation. November 16, 2004;110(20):3234–3238. â•‡ 37. Pache G, Saueressig U, Frydrychowicz A, et al. Initial experience with 64-slice cardiac CT: non-invasive visualization of coronary artery bypass grafts. Eur Heart J. April 2006;27(8):976–980. â•‡ 38. Salm LP, Bax JJ, Jukema JW, et al. Comprehensive assessment of patients after coronary artery bypass grafting by 16-detector-row computed tomography. Am Heart J. October 2005;150(4):775–781. â•‡ 39. Schlosser T, Konorza T, Hunold P, Kuhl H, Schmermund A, Barkhausen J. Noninvasive visualization of coronary artery bypass grafts using 16-detector row computed tomography. J Am Coll Cardiol. September 15, 2004;44(6):1224–1229. â•‡ 40. Burgstahler C, Beck T, Kuettner A, et al. Non-invasive evaluation of coronary artery bypass grafts using 16-row multi-slice com puted tomography with 188 ms temporal resolution. Int J Cardiol. 2006;106(2):244–249. â•‡ 41. Schuijf JD, Poldermans D, Shaw LJ, et al. Diagnostic and prog nostic value of non-invasive imaging in known or suspected coronary artery disease. Eur J Nucl Med Mol Imaging. January 2006;33(1):93–104. â•‡ 42. Senior R, Monaghan M, Main ML, et al. Detection of coronary artery disease with perfusion stress echocardiography using a novel ultrasound imaging agent: two Phase 3 international trials in com parison with radionuclide perfusion imaging. Eur J Echocardiogr. January 2009;10(1):26–35. â•‡ 43. Marwick TH, Case C, Sawada S, et al. Prediction of mortality using dobutamine echocardiography. J Am Coll Cardiol. March 1, 2001;37(3):754–760. â•‡ 44. Marwick TH, Case C, Vasey C, Allen S, Short L, Thomas JD. Prediction of mortality by exercise echocardiography: a strategy for combination with the duke treadmill score. Circulation. May 29, 2001;103(21):2566–2571. â•‡ 45. Klocke FJ, Baird MG, Lorell BH, et al. ACC/AHA/ASNC guidelines for the clinical use of cardiac radionuclide imaging—executive sum mary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/

19

â•‡ 46.

â•‡ 47. â•‡ 48.

â•‡ 49.

â•‡ 50.

â•‡ 51.

â•‡ 52.

â•‡ 53.

â•‡ 54.

â•‡ 55.

â•‡ 56.

â•‡ 57.

â•‡ 58.

â•‡ 59.

â•‡ 60.

â•‡ 61.

â•‡ 62.

ASNC Committee to Revise the 1995 Guidelines for the Clinical Use of Cardiac Radionuclide Imaging). J Am Coll Cardiol. October 1, 2003;42(7):1318–1333. Di Carli MF, Dorbala S, Meserve J, El Fakhri G, Sitek A, Moore SC. Clinical myocardial perfusion PET/CT. J Nucl Med. May 2007;48(5):783–793. Shaw LJ, Iskandrian AE. Prognostic value of gated myocardial per fusion SPECT. J Nucl Cardiol. 2004;11(2):171–185. Iskandrian AS, Chae SC, Heo J, Stanberry CD, Wasserleben V, Cave V. Independent and incremental prognostic value of exercise single-photon emission computed tomographic (SPECT) thallium imaging in coronary artery disease. J Am Coll Cardiol. September 1993;22(3):665–670. Hachamovitch R, Berman DS, Shaw LJ, et al. Incremental prog nostic value of myocardial perfusion single photon emission com puted tomography for the prediction of cardiac death: differential stratification for risk of cardiac death and myocardial infarction. Circulation. 1998;97(6):535–543. Hachamovitch R, Berman DS, Kiat H, et al. Exercise myocardial perfusion SPECT in patients without known coronary artery dis ease: incremental prognostic value and use in risk stratification. Circulation. 1996;93(5):905–914. Berman DS, Kang X, Slomka PJ, et al. Underestimation of extent of ischemia by gated SPECT myocardial perfusion imaging in patients with left main coronary artery disease. J Nucl Cardiol. July 2007;14(4):521–528. Dorbala S, Vangala D, Sampson U, Limaye A, Kwong R, Di Carli MF. Value of vasodilator left ventricular ejection fraction reserve in evaluating the magnitude of myocardium at risk and the extent of angiographic coronary artery disease: a 82Rb PET/CT study. J Nucl Med. March 2007;48(3):349–358. Dorbala S, Hachamovitch R, Curillova Z, et al. Incremental prog nostic value of gated Rb-82 positron emission tomography myocar dial perfusion imaging over clinical variables and rest LVEF. JACC Cardiovasc Imaging. July 2009;2(7):846–854. Di Carli M, Czernin J, Hoh CK, et al. Relation among stenosis severity, myocardial blood flow, and flow reserve in patients with coronary artery disease. Circulation. 1995;91(7):1944–1951. Uren NG, Melin JA, De Bruyne B, Wijns W, Baudhuin T, Camici PG. Relation between myocardial blood flow and the severity of coronary-artery stenosis. N Engl J Med. 1994;330(25): 1782–1788. Anagnostopoulos C, Almonacid A, El Fakhri G, et al. Quantitative relationship between coronary vasodilator reserve assessed by 82Rb PET imaging and coronary artery stenosis severity. Eur J Nucl Med Mol Imaging. September 2008;35(9):1593–1601. El Fakhri G, Kardan A, Sitek A, et al. Reproducibility and accu racy of quantitative myocardial blood flow assessment with 82Rb PET: comparison with 13N-ammonia PET. J Nucl Med. June 12, 2009. Parkash R, deKemp RA, Ruddy Td T, et al. Potential utility of rubidium 82 PET quantification in patients with 3-vessel coronary artery disease. J Nucl Cardiol. July-August 2004;11(4):440–449. Herzog BA, Husmann L, Valenta I, et al. Long-term prognostic value of 13N-ammonia myocardial perfusion positron emission tomogra phy added value of coronary flow reserve. J Am Coll Cardiol. July 7, 2009;54(2):150–156. Schuijf JD, Wijns W, Jukema JW, et al. Relationship between non invasive coronary angiography with multi-slice computed tomog raphy and myocardial perfusion imaging. J Am Coll Cardiol. December 19, 2006;48(12):2508–2514. Di Carli MF, Dorbala S, Curillova Z, et al. Relationship between CT coronary angiography and stress perfusion imaging in patients with suspected ischemic heart disease assessed by inte grated PET-CT imaging. J Nucl Cardiol. November–December 2007;14(6):799–809. Di Carli MF. Applications of PET-CT and SPECT-CT. Atlas of Cardiac Computed Tomography, Companion to Braunwald’s Heart Disease. Elsevier.

Multimodality Imaging in Cardiovascular Medicine

20

â•‡ 63. Sangiorgi G, Rumberger JA, Severson A, et al. Arterial calcification and not lumen stenosis is highly correlated with atherosclerotic plaque burden in humans: a histologic study of 723 coronary artery segments using nondecalcifying methodology. J Am Coll Cardiol. January 1998;31(1):126–133. â•‡ 64. Gaemperli O, Schepis T, Koepfli P, et al. Accuracy of 64-slice CT angiography for the detection of functionally relevant coronary stenoses as assessed with myocardial perfusion SPECT. Eur J Nucl Med Mol Imaging. August 2007;34(8):1162–1171. â•‡ 65. Namdar M, Hany TF, Koepfli P, et al. Integrated PET/CT for the assessment of coronary artery disease: a feasibility study. J Nucl Med. June 2005;46(6):930–935. â•‡ 66. Rispler S, Keidar Z, Ghersin E, et al. Integrated single-photon emission computed tomography and computed tomography cor onary angiography for the assessment of hemodynamically sig nificant coronary artery lesions. J Am Coll Cardiol. March 13, 2007;49(10):1059–1067. â•‡ 67. Mahmarian JJ. Computed tomography coronary angiography as an anatomic basis for risk stratification: deja vu or something new? J Am Coll Cardiol. September 18, 2007;50(12):1171–1173. â•‡ 68. Nagel E, Lehmkuhl HB, Bocksch W, et al. Noninvasive diagnosis of ischemia-induced wall motion abnormalities with the use of highdose dobutamine stress MRI: comparison with dobutamine stress echocardiography. Circulation. February 16, 1999;99(6):763–770. â•‡ 69. Hundley WG, Hamilton CA, Thomas MS, et al. Utility of fast cine magnetic resonance imaging and display for the detection of myocardial ischemia in patients not well suited for second harmonic stress echocardiography. Circulation. October 19, 1999;100(16):1697–1702. â•‡ 70. Wagner A, Mahrholdt H, Holly TA, et al. Contrast-enhanced MRI and routine single photon emission computed tomogra phy (SPECT) perfusion imaging for detection of subendocar dial myocardial infarcts: an imaging study. Lancet. February 1, 2003;361(9355):374–379. â•‡ 71. Klem I, Heitner JF, Shah DJ, et al. Improved detection of coro nary artery disease by stress perfusion cardiovascular magnetic resonance with the use of delayed enhancement infarction imaging. J Am Coll Cardiol. April 18, 2006;47(8):1630–1638. â•‡ 72. Nandalur KR, Dwamena BA, Choudhri AF, Nandalur MR, Carlos RC. Diagnostic performance of stress cardiac magnetic resonance imaging in the detection of coronary artery disease: a meta-analysis. J Am Coll Cardiol. October 2, 2007;50(14):1343–1353. â•‡ 73. Gebker R, Jahnke C, Manka R, et al. Additional value of myocardial perfusion imaging during dobutamine stress magnetic resonance for the assessment of coronary artery disease. Circ Cardiovasc Imaging. 2008;1:122–130. â•‡ 74. Flett AS, Westwood MA, Davies LC, Mathur A, Moon JC. The prognostic implications of cardiovascular magnetic resonance. Circ Cardiovasc Imaging 2009;2:243–250. â•‡ 75. Kuijpers D, van Dijkman PR, Janssen CH, Vliegenthart R, Zijlstra F, Oudkerk M. Dobutamine stress MRI. Part II. Risk stratifica tion with dobutamine cardiovascular magnetic resonance in patients suspected of myocardial ischemia. Eur Radiol. November 2004;14(11):2046–2052. â•‡ 76. Jahnke C, Nagel E, Gebker R, et al. Prognostic value of cardiac magnetic resonance stress tests: adenosine stress perfusion and dobutamine stress wall motion imaging. Circulation. April 3, 2007;115(13):1769–1776. â•‡ 77. Bodi V, Sanchis J, Lopez-Lereu MP, et al. Prognostic value of dipyridamole stress cardiovascular magnetic resonance imaging in patients with known or suspected coronary artery disease. J Am Coll Cardiol. September 18, 2007;50(12):1174–1179. â•‡ 78. Pilz G, Jeske A, Klos M, et al. Prognostic value of normal adenosinestress cardiac magnetic resonance imaging. Am J Cardiol. May 15, 2008;101(10):1408–1412. â•‡ 79. Dall’Armellina E, Morgan TM, Mandapaka S, et al. Prediction of cardiac events in patients with reduced left ventricular ejec tion fraction with dobutamine cardiovascular magnetic resonance

â•‡ 80.

â•‡ 81.

â•‡ 82.

â•‡ 83.

â•‡ 84.

â•‡ 85.

â•‡ 86. â•‡ 87.

â•‡ 88.

â•‡ 89.

â•‡ 90.

â•‡ 91.

assessment of wall motion score index. J Am Coll Cardiol. July 22, 2008;52(4):279–286. Kwong RY, Sattar H, Wu H, et al. Incidence and prognostic implication of unrecognized myocardial scar characterized by cardiac magnetic resonance in diabetic patients without clini cal evidence of myocardial infarction. Circulation. September 2, 2008;118(10):1011–1020. Gibbons RJ, Chatterjee K, Daley J, et al. ACC/AHA/ACP-ASIM guidelines for the management of patients with chronic stable angina: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Patients With Chronic Stable Angina). J Am Coll Cardiol. June 1999;33(7):2092–2197. Douglas PS, Khandheria B, Stainback RF, et al. ACCF/ASE/ACEP/ AHA/ASNC/SCAI/SCCT/SCMR 2008 appropriateness criteria for stress echocardiography: a report of the American College of Cardiology Foundation Appropriateness Criteria Task Force, American Society of Echocardiography, American College of Emergency Physicians, American Heart Association, American Society of Nuclear Cardiology, Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Computed Tomography, and Society for Cardiovascular Magnetic Resonance endorsed by the Heart Rhythm Society and the Society of Critical Care Medicine. J Am Coll Cardiol. March 18, 2008;51(11):1127–1147. Hendel RC, Berman DS, Di Carli MF, et al. ACCF/ASNC/ACR/ AHA/ASE/SCCT/SCMR/SNM 2009 appropriate use criteria for cardiac radionuclide imaging: a report of the American College of Cardiology Foundation Appropriate Use Criteria Task Force, the American Society of Nuclear Cardiology, the American College of Radiology, the American Heart Association, the American Society of Echocardiography, the Society of Cardiovascular Computed Tomography, the Society for Cardiovascular Magnetic Resonance, and the Society of Nuclear Medicine: endorsed by the American College of Emergency Physicians. Circulation. June 9, 2009;119(22):e561–e587. Leber AW, Becker A, Knez A, et al. Accuracy of 64-slice computed tomography to classify and quantify plaque volumes in the proxi mal coronary system: a comparative study using intravascular ultrasound. J Am Coll Cardiol. February 7, 2006;47(3):672–677. Raff GL, Gallagher MJ, O’Neill WW, Goldstein JA. Diagnostic accuracy of noninvasive coronary angiography using 64-slice spiral computed tomography. J Am Coll Cardiol. August 2, 2005;46(3):552–557. Di Carli MF, Kwong RY, eds. Novel Techniques for Imaging the Heart. 1st ed. London: Blackwell Publishing; 2008. Shaw LJ, Hachamovitch R, Berman DS, et al. The economic con sequences of available diagnostic and prognostic strategies for the evaluation of stable angina patients: an observational assessment of the value of precatheterization ischemia. Economics of Noninvasive Diagnosis (END) Multicenter Study Group. J Am Coll Cardiol. March 1999;33(3):661–669. Hachamovitch R, Hayes SW, Friedman JD, Cohen I, Berman DS. Comparison of the short-term survival benefit associated with revascularization compared with medical therapy in patients with no prior coronary artery disease undergoing stress myocardial per fusion single photon emission computed tomography. Circulation. 2003;107(23):2900–2907. Weiner DA, Ryan TJ, McCabe CH, et al. The role of exercise testing in identifying patients with improved survival after coronary artery bypass surgery. J Am Coll Cardiol. October 1986;8(4):741–748. Shaw LJ, Berman DS, Maron DJ, et al. Optimal medical ther apy with or without percutaneous coronary intervention to reduce ischemic burden: results from the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial nuclear substudy. Circulation. March 11, 2008;117(10):1283–1291. Kern MJ, Lerman A, Bech JW, et al. Physiological assessment of cor onary artery disease in the cardiac catheterization laboratory: a sci entific statement from the American Heart Association Committee

C H A P T ER 1

â•‡ 92.

â•‡ 93.

â•‡ 94.

â•‡ 95.

â•‡ 96.

â•‡ 97.

â•‡ 98.

•

Chest Pain: Typical Angina

on Diagnostic and Interventional Cardiac Catheterization, Council on Clinical Cardiology. Circulation. 2006;114:1321–1341. Bech GJ, De Bruyne B, Pijls NH, et al. Fractional flow reserve to determine the appropriateness of angioplasty in moderate coronary stenosis: a randomized trial. Circulation. 2001;103:2928–2934. Pijls NH, van Schaardenburgh P, Manahoran G, et al. Percutaneous coronary intervention of functionally nonsignificant stenosis: 5-year follow-up of the DEFER study. 2007;49:2105–2111. Tonino PA, De Bruyne B, Pijls NH, et al. Fractional flow reserve versus angiography for guiding percutaneous coronary interven tion. N Engl J Med. January 15, 2009;360(3):213–224. Chamuleau SAJ, Meuwissen M, Koch KT, et al. Usefulness of frac tional flow reserve for risk stratification of patients with multivessel coronary artery disease and an intermediate stenosis. Am J Cardiol. 2002;89:377–380. Gibbons RJ, Balady GJ, Bricker JT, et al. ACC/AHA 2002 guideline update for exercise testing: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1997 Exercise Testing Guidelines). Circulation. 2002;106(14):1883–1892. Mieres JH, Shaw LJ, Arai A, et al. Role of noninvasive testing in the clinical evaluation of women with suspected coronary artery disease: consensus statement from the Cardiac Imaging Committee, Council on Clinical Cardiology, and the Cardiovascular Imaging and Intervention Committee, Council on Cardiovascular Radiology and Intervention, American Heart Association. Circulation. February 8, 2005;111(5):682–696. Fraker TD Jr., Fihn SD, Gibbons RJ, et al. 2007 Chronic angina focused update of the ACC/AHA 2002 guidelines for the manage ment of patients with chronic stable angina: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines Writing Group to develop the focused update of the 2002 guidelines for the management of patients with chronic sta ble angina. J Am Coll Cardiol. December 4, 2007;50(23):2264–2274.

21

â•‡ 99. Kwok JM, Miller TD, Hodge DO, Gibbons RJ. Prognostic value of the Duke treadmill score in the elderly. J Am Coll Cardiol. May 1, 2002;39(9):1475–1481. 100. Berman DS, Hachamovitch R, Shaw LJ, Germano G, Hayes S. Nuclear cardiology. In: Fuster VKS, O’Rourke RA, Wellens HJJ, eds. Hurst’s The Heart. New York, NY: McGraw-Hill Companies; 2004:525–565. 101. Marwick TH, ed. Application of stress echocardiography to the prediction of outcomes. In: Stress Echocardiography: Clinical Application in the Diagnosis and Management of Coronary Artery Disease. Norwell, MA: Kluwer Academic Publishers; 2003:167–206. 102. Giri S, Shaw LJ, Murthy DR, et al. Impact of diabetes on the risk strat ification using stress single-photon emission computed tomography myocardial perfusion imaging in patients with symptoms suggestive of coronary artery disease. Circulation. January 1, 2002;105(1):32–40. 103. Rakhit DJ, Armstrong KA, Beller E, Isbel NM, Marwick TH. Risk stratification of patients with chronic kidney disease: results of screening strategies incorporating clinical risk scoring and dobutamine stress echocardiography. Am Heart J. August 2006;152(2):363–370. 104. Hakeem A, Bhatti S, Dillie KS, et al. Predictive value of myocardial perfusion single-photon emission computed tomography and the impact of renal function on cardiac death. Circulation. December 9, 2008;118(24):2540–2549. 105. Al-Mallah M, Hachamovitch R, Dorbala S, Di Carli MF. Incremental prognostic value of myocardial perfusion imaging in patients referred to stress SPECT with renal dysfunction. Circ Cardiovasc Imaging. 2009;in press. 106. Scanlon PJ, Faxon DP, Audet AM, et al. ACC/AHA guidelines for coronary angiography: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines (Committee on Coronary Angiography). Developed in collaboration with the Society for Cardiac Angiography and Interventions. J Am Coll Cardiol. May 1999;33(6):1756–1824.

2

Atypical Chest Pain and Other Presentations of an Intermediate Likelihood of Obstructive Coronary Artery Disease

jâ•‡General Considerations in Pretest Evaluation

of Patients with Atypical Chest Pain

AIDEN ABIDOV Da NIEL S. B ERMa N RO RY H aC haMOVITC h According to the 2008 Heart Disease and Stroke Statistics Update [1], an estimated 80 700 000 American adults (1 in 3) have 1 or more types of cardiovascular diseases (CVD). Approximately 16 000 000 of these patients have established coronary artery disease (CAD), and many more have undiagnosed coronary lesions that may represent as either atypical symptoms or, in many cases, manifest as either myocardial infarction with irreversible damage to myocardium, or cardiac death. Nearly 2400 Americans die of cardiac conditions each day, an average of 1 death every 37 seconds. Cardiovascular mortality claims approximately as many lives each year as cancer, chronic lung disorders, accidents, and diabetes mellitus combined [2]. According to the Statistics Update, in 2005 there were 6 734 000 outpatient department visits with a primary diagnosis of cardiovascular disorder; approximately 1 of every 6 hospital stays, or almost 6 million, resulted from CVD [1]. The total inpatient hospital cost for cardiac disorders was $71.2 billion, approximately one-fourth of the total cost of hospital care in the United States. This huge social burden requires us to seek further improved diagnostic modalities and algorithms, allowing to identify patients with early and thus more easily correctable forms of disease as well as to distinguish those with atypical presentations and intermediate likelihood of CAD. Chest pain (CP) is one of the most frequent complaints encountered in clinical practice, both acutely in the 22

Emergency Department (ED) and as a chronic symptom during the outpatient clinical encounters. Since consequences related to a possibility of missed and untreated acute coronary syndromes (ACS) or chronic obstructive CAD might be associated with a potentially fatal outcome, clinicians tend to overdiagnose and overinvestigate the symptomatology. In the modern algorithms, initial steps in the evaluation of patients with CP include important procedures focused on exclusion of CAD as a cause of pain [3]; this includes a CAD-oriented history, physical examination, and resting ECG, with 2 or more sets of cardiac enzymes if the presentation is either acute or subacute. A simple set of 3 questions has been recommended to differentiate a typical anginal CP from either atypical angina or nonanginal CP [4,5] (Table 2.1). These 3 large jâ•…Table 2.1â•…Clinical classification of chest pain Typical Angina (Definite)

Atypical Angina (Probable)

Noncardiac Chest Pain

1.â•‡Substernal chest discomfort with a characteristic quality and duration that is: 2.â•‡provoked by exertion or emotional stress

Meets 2 of the given Meets 1 or none of characteristics the typical anginal characteristics

3.â•‡relieved by rest or NTG. NTG, nitroglycerin. Reproduced with permission from Ref. 3; modified from Ref. 4.

C H A P TER 2

•

Atypical Chest Pain and Other Presentations

categories of CP along with the patients’ age and gender are widely employed as the predictors of pretest likelihood of obstructive CAD, estimated using either an original Diamond–Forrester [4,6], CASS [7], or modified ACC/ AHA classification [3], the latter of which is a simplification of the Diamond publications. In more sophisticated analysis of likelihood of CAD, the number and type of risk factors should also be taken into account [8]. Atypical angina in the 40 to 70 years age group is associated with an intermediate pretest likelihood of CAD (22%–72%, depending on age and gender). The intermediate likelihood of CAD has been defined in various ranges, extending from 10% to 90% [3], 15% to 85% [9], 20% to 80%, and 30% to 70%; cardiac imaging in these patients provides the most significant diagnostic yield and helps in clinical decision-making process (Figure 2.1). In patients with a low likelihood of CAD, even when symptomatic, the likelihood of disease is so low that further testing is not considered warranted. In patients with a high likelihood of CAD, the diagnosis of CAD is usually considered established. Additional testing, if needed, is performed for riskstratification purposes and for guiding patient management, rather than for diagnostic purposes.

23

There are several clinical categories of patients who are falling into the category of intermediate likelihood of CAD. In general, these include not only most patients with atypical angina, but also younger patients, particularly women, with typical angina, and older patients, particularly men, with nonanginal chest pain. This chapter discusses the use of stress imaging for ischemia and cardiac CT examinations in patients with atypical angina and other presentations in which there is an intermediate pretest likelihood of obstructive CAD. Within our discussion of imaging for ischemia, we have chosen to limit it to nuclear cardiology methods. For application in patients with an intermediate likelihood of CAD, however, other stress imaging modalities including echocardiography and cardiac magnetic resonance have clearly been shown to have widespread application. When a stress imaging modality is being selected, factors such as availability of equipment, technical expertise, and clinical expertise found at an individual testing site are considered more important than differences in the capabilities of the modalities in selecting a test for a given patient. Clinical application of the advanced imaging modalities can significantly increase an effectiveness of the clinical

F i g u r e 2 . 1â•…Clinical case of the patient with low-intermediate pretest likelihood of coronary artery disease (CAD): a 50-year-old female without history of prior CAD, presenting to ED with atypical chest pain and exertional shortness of breath. Her prior medical history is remarkable for hypertension and smoking. Her resting ECG demonstrated sinus rhythm, isolated premature ventricular beats and diffuse nonspecific T-wave abnormalities. She was referred for the dual isotope rest-stress myocardial perfusion imaging. Rest perfusion was normal (bottom rows). The patient performed treadmill exercise for a total of 4:23 minutes and achieved 130 beats per minute (76% of the maximal predicted heart rate). The exercise was discontinued due to a worsened shortness of breath and chest pain. There were borderline ischemic ECG changes noted. Poststress perfusion images (top rows) demonstrate large area of the reversible perfusion defect involving distal and midanterior and antero-lateral segments seen to be reversible on rest images (bottom rows). The patient was referred for invasive coronary angiography which demonstrated presence of 90% stenosis of the large first diagonal branch, moderate disease of the left circumflex artery and 50% to 75% proximal and mid right coronary artery. The patient underwent successful percutaneous coronary intervention and stent implantation to first diagonal branch, with subsequent symptomatic improvement. SAX, short axis; VLA, vertical long axis; HLA, horizontal long axis.

24

decision-making process in patients with atypical presenting symptoms and others with an intermediate pretest likelihood of CAD, by several mechanisms: (1) identifying patients at increased risk who should undergo invasive evaluation of their coronary arteries and possible revascularization, (2) revealing those who are at low risk of cardiac events and/or have a low posttest likelihood of obstructive CAD, and thus, potentially eliminating need for further testing, and reassuring worried patients and families in their favorable prognosis, (3) switching attention of the clinicians from cardiac diagnostic path to identifying a need in evaluating other systems in order to find a clear noncardiac reason for CP, at times utilizing pathological findings discovered on the cardiac scan images (tumors, pericardial, and pleural disorders, pulmonary embolism, aortic pathology, hiatal hernia, etc.), (4) identifying potential targets for revascularization in patients who are candidates for invasive coronary angiography (ICA), and (5) providing follow-up in patients who develop atypical symptoms post-revascularization. The chapter first reviews the applications of nuclear cardiology studies in these patients, followed by the review of applications of cardiac computed tomography (CT), and finishes with a discussion of an integrated approach to these assessments, with the choice in test depending on the initial pretest likelihood of CAD.

Multimodality Imaging in Cardiovascular Medicine

prone and supine imaging are also considered to be associated with improvement in reader confidence. With respect to vasodilator positron emission tomoÂ� graphy (PET) MPI, a meta-analysis of 19 recent studies has recently been published reporting 92% sensitivity and 85% specificity [16] for detecting CAD. Bateman et al have compared the diagnostic accuracy of PET versus SPECT in 2 large cohorts undergoing blinded interpretation [17]. Both sensitivity and specificity are higher with PET, and overall accuracy is higher in men and women as well as in obese and nonobese patients (Figure 2.2). The accuracy of PET has been reported to also be higher for identifying patients with multivessel and left main disease (48% vs. 71%, P 5 .03) (Figure 2.3). The most likely reasons for higher sensitivity and specificity of PET versus SPECT are the routine use of robust attenuation correction and the greater linearity of myocardial uptake versus flow of the PET perfusion agents than of the currently available Tc-99m agents. Also, vasodilator PET using Rb-82, imaging is performed during as opposed to after pharmacologic stress, providing the opportunity to evaluate peak-stress ventricular function. Another attribute of PET MPI that has not yet been fully explored is the ability of this modality to assess absolute myocardial perfusion and rest/stress flow reserve. Referral or Verification Bias

A major limitation in assessing the diagnostic accuracy of SPECT or PET MPI for CAD is current clinical reality jâ•…D I AGNOS T IC A CC URACY OF SPECT that the test result influences the decision to perform ICA, AN D PET M PI: GENERAL ASP ECTS an invasive gold standard, thereby biasing the population The accuracy of diagnostic testing for CAD is defined available for analysis of sensitivity and specificity. Using a clinically on the basis of sensitivity and specificity for multivariable analysis, Hachamovitch et al have recently identification of angiographically significant stenoses, most demonstrated that the extent of ischemia by SPECT MPI commonly employing either a 50% or a 70% diameter-Â� provided 83% of the information appearing to determine narrowing cutoff. ACC/AHA/ASNC guidelines on car- referral for catheterization [18]. Thus, in estimating the diac radionuclide imaging report a pooled sensitivity and true sensitivity and specificity of noninvasive testing, this specificity of 87% and 73% for exercise single photon referral or workup bias must be taken into account [19]. emission computed tomography (SPECT) myocardial As routine patient workup results in preferential Â�catheterization perfusion imaging (MPI) (based on 33 published studies) of patients with abnormal (ischemic) test results, this referand 89% and 75% for vasodilator SPECT MPI (based ral bias leads to an overestimation of test Â�sensitivity and a on 17 published studies) for detection of CAD [10]. An reduction in test specificity with the latter showing the most improved predictive accuracy by nuclear testing over Â�dramatic change. pretest information and ECG stress testing has been consistently documented [11]. In women, the specificity of Normalcy Rate SPECT MPI is increased with gated 99mTc-based agents compared to ungated 201Tl SPECT MPI, attributed to The normalcy rate has been advocated as a means of assessless susceptibility to breast attenuation of gated SPECT ing test specificity without requiring the angiographic stanMPI with 99mTc-based agents [12]. The ability to immedi- dard [20]. Normalcy rate has been defined as the percentage ately reacquire SPECT images with 99mTc-based agents of patients with normal test results in a population with a low when either attenuation or motion artifact is suspected likelihood of disease, usually employing a ,5% criterion. The further increases specificity with these agents [13,14]. recent ACC/AHA/ASNC guidelines report a normalcy rate Improvements in specificity have also been reported with for SPECT MPI of 91%. Even in obese patients, normalcy the use of attenuation correction algorithms [15]. The rates .90% have been reported when attenuation correction use of ECG gating attenuation correction, and combined or combined supine/prone imaging is employed [13].

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2 . 2 â•…Clinical case of the 69-year-old female patient, presenting with atypical chest pain and no prior coronary artery disease. Initially, the patient underwent stress-rest Tc-99 sestamibi single photon emission computed tomography myocardial perfusion imaging which was equivocal with possible soft tissue attenuation (upper plate). Subsequent stress-rest Rb-82 positron emission tomography (lower plate) was perfectly normal. Figure

F i g u r e 2 . 3 â•…Diagnostic performance of cardiac positron emission tomography (PET) compared to single photon emission computed tomography (SPECT) myocardial perfusion imaging by gender, body mass index (BMI) and in multivessel disease (MVD). Reproduced with permission from the Ref. 17.

Diagnostic Impact of MPI In the lower range of intermediate CAD likelihood (eg, 0.15–0.50), many advocate the use of exercise tolerance testing (ETT) alone, without imaging [3]. Although patients with pre-ETT likelihood of CAD in the 0.50 to 0.85 range could also be considered candidates for ETT alone, [10,21]

many experts consider SPECT or PET MPI to be the appropriate first test since a negative ETT would not result in a low CAD likelihood. Patients with an indeterminate CAD likelihood after ETT (eg, intermediate-risk Duke treadmill score [10,22], are candidates for MPI. Patients with ECG uninterpretable for ETT [eg, left ventricular hypertrophy

26

(LVH), digoxin, Wolff-Parkinson-White (WPW), .1 mm resting ST depression, LBBB, permanent pacemaker, etc.] are candidates for MPI rather than ETT. As noted below, the development of CT coronary angiography may alter this approach, possibly becoming the first diagnostic test toward the lower part of the pretest likelihood spectrum.

Multimodality Imaging in Cardiovascular Medicine

considered likely that the relationships between PET MPI subsequent patient outcomes will be at least as strong as those observed with SPECT MPI. In the discussion that follows, the principles applied to SPECT MPI are considered equally applicable to PET MPI.

Incremental Prognostic Value jâ•…RISK ASS ESSMENT Principles of Risk Stratification A widely used paradigm in patient management is that of a risk-based approach to patients with suspected CAD in whom symptoms are nonlimiting. In patients referred directly to catheterization for any reason, pericatheterization SPECT or PET MPI may serve to identify the culprit lesion. However, in less symptomatic patients, precatheterization risk assessment is more important. With a riskbased approach, the focus is not on predicting the presence of CAD but on identifying patients at risk for specific, potentially preventable adverse events. Subsequent management focuses on reducing the risk of these outcomes, whether cardiac death, nonfatal MI or CAD progression. Invasive diagnostic and therapeutic procedures are limited to those patients who are most likely to benefit from them. The basic concept underlying the use of nuclear testing for risk stratification is that patients known to be at high or low risk for events would not need risk stratification with nuclear imaging since they are already stratified. However in those patients with uncertain clinical presentation and in intermediate likelihood if CAD and/or uncertain prognostic risk, MPI is able to provide a robust data, allowing individual assessment and management of each patient with challenging symptoms.

Risk Thresholds For the purposes of risk assessment, it has been proposed that low risk be defined as a ,1% annual cardiac mortality rate and intermediate risk could be defined by the range of 1% to 3% per year [21]). Since the mortality risk for patients undergoing revascularization is at least 1%, symptomatic patients with a less than 1% annual mortality rate would not appear to be candidates for revascularization to improve survival. It has been suggested that a .3% annual mortality rate is a threshold to identify patients with symptoms whose mortality rate can be improved by coronary artery bypass surgery (CABS) [23]. Based on combined published literature, SPECT or PET MPI is most appropriate in patients with .l% annual mortality and intermediate or high likelihood of CAD. There is far less written about the prognostic implications of PET MPI than for SPECT MPI. However, given the overall higher accuracy of PET MPI for detecting obstructive CAD, it is

The clinical value of MPI for prognostic assessment of CAD results from the incremental or added prognostic information yielded by this modality over all data available prior to the test (clinical, historical, and stress data), as first demonstrated by Ladenheim et al [24].

Event Risk After a Normal Scan A synthesis of available data reveals that a normal scan is generally associated with a ,1% annual risk of cardiac death or MI. A meta-analysis of the prognostic value of a normal stress perfusion scan (N 5 29 788) reveals that the annual risk of MI or cardiac death after a normal perfusion scan is 0.5% (95% CI 0.3%–0.7%). [25] This low event rate is critical in applying nuclear test information to risk stratification, since in the absence of symptoms, patients with normal perfusion scans can be managed conservatively. This approach includes follow-up for signs of clinical worsening and treatment of cardiac risk factors and related symptoms. Despite the low risk associated with normal SPECT studies, a limited number of studies have reported somewhat higher levels of risk. Recently, a study examining predictors of risk and its temporal characteristics in a series of 7376 patients with normal stress SPECT MPI identified the use of pharmacologic stress and the presence of known CAD (Figure 2.4A), diabetes mellitus (in particular, female diabetics), and advanced age as markers of increased risk and shortened time to a hard event (eg, risk in the first year of follow-up was less than in the second year) [26]. Hence, a dynamic temporal component of risk was present and the existence of a warranty period for specific patient groups was defined (Figure 2.4B). This increased risk after normal SPECT in a small subset of patients is due to the presence of comorbidities that increase baseline risk of all patients (diabetes mellitus, age, inability to exercise, prior CAD, dyspnea) as the presenting symptom [5] and, in some patients, the possibility that extensive CAD was missed due to balanced reduction of flow. The latter would lead to a severe underestimation of the extent of ischemia by SPECT MPI. Although many of these patients can be detected by ancillary markers—such as LV transient ischemic dilation [27], a rest to post stress fall in LVEF, or increased lung tracer uptake—in some patients with high-risk anatomic lesions, SPECT MPI will appear completely normal. In a recent study reported from our center, 13% of patients with left main coronary artery disease of sufficient severity to warrant referral for revascularization had minimal findings (equivocal) on SPECT MPI (Figure 2.5) [28].

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F i g u r e 2 . 4 â•… Annual rates of hard events in patients after normal single photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI). The following subgroups are shown: women versus men, patients with and/without history (Hx) of coronary artery disease (CAD) and patients undergoing adenosine versus exercise stress. A significant risk is noted in the patients with Hx CAD, *P , .001. (A) Rates of hard events in first and second years of follow-up after normal SPECT MPI. Four examples are given: a 50-year-old male undergoing exercise stress with no history of CAD, an 80-year-old male undergoing adenosine stress with no history of CAD, a 50-year-old male with a history of CAD, and an 80-year-old male with a history of CAD. In patients with no history of CAD, the event rates in the first and second years after SPECT MPI are not different; however, the event rate for normal SPECT MPI goes up significantly with increased patient risk. In patients with previous CAD, the event rates in the second year after SPECT MPI were greater than in the first year, and there is additional increase in the event rate with clinical risk (B). Reproduced with permission from Ref. 26.

Event Risk with Abnormal Scans The relationship of varying extent and severity of perfusion abnormalities with cardiac outcomes has been reported in a variety of patient subsets [3,21,29,30] consistently; increasing scan abnormality is associated with an increasing risk of cardiac events. Although both reversible and fixed stress perfusion defects are predictors of prognosis, those at highest risk of cardiac events are patients with extensive stress abnormalities. Prognosis is also dependent on both the severity and extent of perfusion defects, correlates of the stenosis magnitude, and the amount of myocardium subtended by the stenosed vessels [31]. As these parameters worsen, risk of major cardiac outcomes increase (Figure 2.6). Annual cardiac event rates have been reported to range from 0.3% to 4.2% for patients with normal, mild, moderate, and severely abnormal perfusion scans, with significant variability associated with each level of defect extent and severity. Similar findings have been described with 201Tl and with 99mTc tetrofosmin [25,32].

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F i g u r e 2 . 5 â•…Detection rates of LM CAD in all patients with high risk of abnormality by perfusion and nonperfusion data on gated myocardial perfusion single photon emission computed tomography. *, P , .05 versus greater than 10% myocardium at stress. †, P , .001. Abnl WM, abnormal wall motion; EF, ejection fraction; LM CAD, left main coronary artery disease; Myo, % myocardium hypoperfused at stress; TID, transient ischemic dilation. Reproduced with permission from the Ref. 28.

F i g u r e 2 . 6 â•…The prognostic value of the stress perfusion defect (% myocardium abnormal at stress) (horizontal axis) is plotted versus the cardiac death rate (vertical axis) for 17 and 20 segment scoring systems. The cardiac mortality rate rises steadily with either approach, and there are no significant differences between the 17 and 20 segment systems when analyzed in this normalized manner. Based on data from Ref. 30. Reproduced with permission from Ref. 83.

Mildly Abnormal SPECT MPI Previously, we had described patients with mildly abnormal scans to be at intermediate risk for MI but at low risk for subsequent mortality [33]. Although the overall observation holds true for groups of patients, risk assessment in an individual patient is improved by taking into account findings other than those of the scan. The presence of high-risk clinical or historical markers identifies a subset of patients at greater risk for any level of scan abnormality, that is, prescan data yield incremental prognostic information

Multimodality Imaging in Cardiovascular Medicine

Risk-adjusted Cardiac Mortality (%)

28

20

Exercise

jâ•… Table 2.2â•… Summary MPI variable: Perfusion Scale

16

Adenosine

Categorya

SSS

12

Age 60-80

None

0–1

,2

Equivocal

2–3

2–4

Mild

4–6

5–9

Moderate

7–13

10–19

Severeb

14

20

Age <60 Age>80 DM W

8

DM M 4

nonDM W nonDM M

0

5-10%

>20% 10-20% % myocardium Ischemic

F i g u r e 2 . 7 â•…Rates of risk-adjusted cardiac mortality as a function of

% myocardium ischemic (5%–10%, 10%–20% and .20%) in medically treated patients [exercise vs. adenosine stress, patients aged ,60 years, 60 to 80 years and .80 years, diabetic (DM) men (M) versus women (W) and nondiabetic men and women]. Although predicted cardiac mortality increases with increasing % myocardium ischemic, the rates at any level of ischemia varies widely at any level of ischemia as a function of clinical information. Based on data from Ref. 18. Reproduced with permission from Ref. 82.

% Defect

Nonperfusion High-Risk Markers, transient ischemia dilation (TID) increased lung uptake, increased right ventricular (RV) uptake, ejection fraction (EF) ,45%, 5% fall in EF, stress-induced wall motion abnormality, severe defect (score 3 or 4) [28,83,87]. Increase category by 1 level if any nonperfusion high-risk markers. EF  35%, high risk irrespective of perfusion category.

a

b

over SPECT MPI results (Figure 2.7) [18,33–35]. Hence, although patients with mildly abnormal SPECT MPI results generally are at low risk of cardiac death, the risk is higher in a variety of subgroups with significant comorbidities and presentations (eg, advanced age, diabetes mellitus, atrial fibrillation, pharmacologic stress, reduced left ventricular function, dyspnea) [5,36]. In addition to these conditions, increased risk in patients with mildly abnormal scans is likely if there are ancillary high risk makers. Table 2.2 shows categories for the magnitude of myocardial perfusion abnormality on SPECT MPI including consideration of these high risk markers.

Moderate to Severely Abnormal SPECT MPI This category of scan abnormality is associated with the highest levels of risk. Anticipated patient risk is greatest in patients with high risk cardiovascular comorbidities, increased left ventricular size/reduced LV function, extensive scar, and so on. As discussed below, patients in this SPECT MPI category with extensive ischemia are most likely to benefit from revascularization as opposed to conservative management. Using MPI for Medical Decision Making: Assessing Risk Versus Potential Survival Benefit Beyond risk-stratification, optimal selection of patient treatment is based on reasonable estimates of potential patient benefit with one treatment option versus an alternative. To this end, a major step forward is the recently evolved paradigm indicating that rather than identify patient risk, the role of MPI in a testing strategy is the identification of patients who may accrue a survival benefit from revascularization as opposed to those who lack a survival benefit from this procedure and, conversely,

F i g u r e 2 . 8 â•…Relationship between % myocardium ischemic and log of the hazard ratio in 10 647 patients without known CAD treated either with medical therapy (Rx) (dashed line) or early revascularization (,60 days post single photon emission computed tomography myocardial perfusion imaging; solid line) based on multivariable modeling. In the setting of little or no ischemia, medical therapy is associated with superior survival; with increasing amounts of ischemia a progressive survival benefit with revascularization (Reverse) over medical therapy is present. 95% confidence intervals are shown by the closely dotted lines. Reproduced with permission from Ref. 18.

which patients will have a superior survival with medical therapy alone. In a study examining 10 627 patients without prior MI or revascularization who underwent stress SPECT MPI, a survival benefit was present for patients undergoing medical therapy versus revascularization in the setting of no or mild ischemia, whereas patients undergoing revascularization had an increasing survival benefit over patients undergoing medical therapy when moderate to severe ischemia was present (.10% of the total myocardium ischemic) (Figure 2.8) [18]. This survival benefit was particularly striking in higher-risk patients

Atypical Chest Pain and Other Presentations

1 0

30% 20%

–2

10%

change in risk with revasc

0% 0

20%

40%

60%

80%

100%

Gated SPECT EF Figure 2.9â•… Relationship between gated single photon emission computed

tomography ejection fraction (EF) and log of the hazard ratio in 5366 patients based on multivariable modeling. Solid lines represent predicted survival for 0%, 10%, 20% and 30% myocardium ischemic in patients treated medically. Dashed lines represent predicted survival for patients treated with revascularization for all values of % myocardium ischemic. Overall, risk increased with decreasing EF. For any value of EF, however, risk also increased as % myocardium ischemic increased, indicating an incremental value for % myocardium ischemic over EF. Compared to risk in patients treated medically, risk in patients undergoing early revascularization was independent of the % myocardium ischemic present (as evidenced by a single (dashed) line representing survival after revascularization for all degrees of ischemia). Risk in the early revascularization patients was similar to the risk of medically treated patients with 10% myocardium ischemic, throughout the range of EF. Reproduced with permission from Ref. 38.

frequently presenting with atypical symptoms (elderly, requiring adenosine stress, and women, especially diabetics). These results have been extended to incorporate gated SPECT MPI EF information [38]. Comparing the roles in risk assessment of perfusion and function data, although EF, percent myocardium ischemic and the percent myocardium fixed are all predictors of cardiac death, the former is by far the best predictor of cardiac mortality. On the other hand, only inducible ischemia identified patients who would benefit from revascularization in comparison to medical therapy (Figure 2.9). With increasing amounts of ischemia, increasing survival benefit for revascularization over medical therapy was found, irrespective of EF. On the other hand, as shown by previous randomized control trials, the absolute benefit to be gained from a therapeutic strategy, for any level of ischemia present, is proportional to underlying patient risk. Thus, in assessing treatment options in an individual patient, cardiac risk factors, comorbidities, and EF all have to be considered along with ischemia in order to determine the potential advantages of a specific therapeutic strategy. Use of SPECT MPI in Guiding Decisions for Catheterization and Revascularization Several investigators have shown that SPECT MPI results appear to heavily influence post-SPECT MPI clinical decision making. Among patients with normal scans, only a small proportion undergo early post-SPECT MPI cardiac

1.0 0.8

Atyp

0.6

Asx

0.4

2

Medical Rx: % ischemic

A

–1

log Relative Hazard

3

C

TAP

0.2

Revasc

0.0

4

B

29

Probability of Referral to Early Revasc

•

C H A P TER 2

0

12.5%

25%

37.5%

50%

% Total Myocardium Ischemic F i g u r e 2 . 1 0 â•…Relationship between % myocardium ischemic and

probability of referral to early revascularization (,60 days post single photon emission computed tomography myocardial perfusion imaging. Results based on multivariable modeling in 10 647 patients. In this study, % myocardium ischemic was most strongly associated with referral to revascularization (83% of all information used for decision making). Further, patients’ presenting symptoms also influenced this process as evidenced by greater likelihood of referral at any level of ischemia with typical (TAP) versus atypical (Atyp) versus asymptomatic (Asx) patients. Reproduced with permission from Ref. 18.

catheterization, usually as a result of clinical symptomatology [39]. As first shown by Hachamovitch and colleagues, the extent and severity of reversible defects shown by the SPECT MPI result is the dominant factor driving subsequent resource utilization, regardless of the presenting symptoms [18] (Figure 2.10). Regarding the cost-Â�effectiveness of this approach, Shaw et al [40] in a multicenter study of 11 249 patients, showed that a strategy of SPECT MPI with selective subsequent catheterization produced a substantial reduction (31%–50%) in costs for all levels of pretest clinical risks compared to a direct catheterization approach (Figure 2.11), with essentially identical outcomes as assessed by cardiac death and myocardial infarction rates. Importantly, in the SPECT MPI strategy, rates of revascularization, cardiac catheterization after normal SPECT MPI, and the frequency of normal coronary angiographic findings were significantly reduced [33,41]. A recent landmark study, the Clinical Outcomes UtilizÂ� ing Revascularization and Aggressive Drug Evaluation (COURAGE) trial [42] was designed to assess a superiority of PCI coupled with optimal medical therapy in reducing the risk of death and nonfatal myocardial infarction in patients with stable CAD, as compared with optimal medical therapy alone. The population in the study was highly selected: out of 35 539 screened patients, only 2287 were enrolled in the study. The patients were randomized to undergo PCI with optimal medical therapy (PCI group, n 5 1149 patients) and 1138 to receive optimal medical therapy alone (OMT group, n 5 1138 patients). Patients were followed for an average of 4.5 years. OMT patients were allowed to cross over to revascularization

30

F i g u r e 2 . 1 1 â•…Comparative cost between screening strategies employing direct catheterization (Cath) and myocardial perfusion imaging (MPI) with selective Cath. Low, Int, and High represent low-risk, intermediaterisk, and high-risk subsets of the patients with stable angina. Shown are the initial diagnostic costs (solid bars) and follow-up costs including costs of revascularization (gray bars). A 30% to 41% reduction in costs was noted in each category. Hard event rates were similar with the 2 strategies, but the revascularization rate was twice as high in the direct cath group. Reproduced with permission from Ref. 41.

if they had progressive or refractory symptoms. The main results of the trial, published in the New England Journal of Medicine in 2007, have shown that as an initial management strategy in patients with stable CAD, PCI did not reduce the risk of death, MI, or other major cardiovascular events when added to OMT. The authors concluded that “as an initial management approach, OMT without routine PCI can

Multimodality Imaging in Cardiovascular Medicine

be implemented safely in the majority of patients with stable CAD. However, approximately one-third of these patients may subsequently require revascularization for symptom control or for subsequent development of an ACD.” Since the COURAGE Trial showed no survival advantage with the addition of PCI, the question must be raised as to whether stress imaging has a role in guiding selection of patients for revascularization. If patients do not benefit from revascularization, and catheterization is not needed, stress imaging would also not be needed to identify the potential catheterization candidate. However, as a part of the COURAGE study, an important substudy [43] addressed how SPECT MPI testing may shape clinical outcomes. In this substudy of 314 patients in whom both prerandomization and 6 to 18 month postrandomization SPECT MPI was performed, patients assigned to PCI and OMT demonstrated significantly greater ischemia reduction when compared to patients receiving OMT alone [PCI 1 OMT: 33% (n 5 159); OMT alone: 19% (n 5 155); P 5 .0004]. Importantly, among the relatively smaller subset of patients with moderate-to-severe pretreatment ischemia, a significantly greater proportion showed significant ischemia reduction (5% reduction in ischemic myocardium) with a strategy of PCI 1 OMT as opposed to OMT (78% vs. 52%; P 5 0.007). Hence, despite the lack of improved survival with PCI 1 OMT versus OMT alone in the main COURAGE study [41], the former may be a superior approach to reduce ischemic burden, particularly in patients with extensive ischemia. Thus, the substudy provides supportive evidence that imaging of myocardial ischemia could affect patient outcomes through guiding decisions for revascularization. Of note, the posttherapy residual ischemia was strongly predictive of outcomes in both the PCI and the OMT alone groups (Figure 2.12). Hopefully, this hypothesis

F i g u r e 2 . 1 2 â•… Results of the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation Nuclear Substudy [43]: Kaplan–Meier survival

for patients by residual ischemia including 0%, 1% to 4.9%, 5% to 9.9%, and 10% ischemic myocardium, respectively, after 6 to 18 months of percutaneous coronary intervention 1 OMT or OMT. Overall event-free survival was 100%, 84.4%, 77.7%, and 60.7%, respectively, for 0%, 1% to 4.9%, 5% to 9.9%, and 10% ischemic myocardium (P , .001). A. In a risk-adjusted Cox model (controlling for randomized treatment), this difference was not significant (P 5 .09). B, Unadjusted (dark gray bars) and risk-adjusted (light gray bars) hazard ratios for the extent and severity of residual ischemia at 6 to 18 months of follow-up. Reproduced with permission from Ref. 43.

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generating research will lead to a randomized clinical trial testing whether patients with moderate-to-severe ischemia benefit from a revascularization approach.

jâ•…M PI I N EVAL U ATI ON OF AC UT E CHEST PA I N Because of the relationship to closure of a coronary artery, SPECT MPI is an effective means of detecting patients with acute ischemic syndromes. Although the diagnosis of acute MI is frequently straightforward, in many patients it is not. For patients with normal or nondiagnostic initial ECGs on presentation to the ED, an important clinical problem is to distinguish those with ACS requiring hospital admission from those who may be safely discharged. Because most patients presenting with acute chest pain subsequently rule out for acute ischemic syndromes, chest pain units have been instituted for the acute evaluation of chest pain patients presenting to the ED.99mTc-sestamibi or tetrofosmin SPECT MPI, with injection during chest pain, provides an excellent opportunity to reduce clinical indecision in the acute evaluation of chest pain (Figure 2.13). A number of studies have demonstrated a role for SPECT

31

MPI in the initial evaluation of these patients. A normal rest 99mTc-sestamibi or tetrafosmin SPECT MPI study has a 99% negative predictive value. A prospective, randomized, controlled multicenter trial examined whether incorporating acute rest SPECT MPI into an ED evaluation strategy of patients presenting with suspected acute ischemia improved initial ED triage [44]. A significant reduction in hospitalization was noted in patients with normal SPECT MPI studies. Guidelines for MPI in the ED Several considerations are important for effective application of SPECT or PET MPI in the ED. In patients with prior MI, the studies are generally not useful, unless the results of previous MPI are immediately available for comparison. Also, combined assessment of perfusion and function should be routinely performed in order to minimize the false-negative rate. Combined supine and prone imaging or attenuation correction is very useful in reducing the false-positive rate. An abnormal rest MPI study triggers admission and therapy for an acute ischemic syndrome. Patients with normal rest studies, after negative enzymes are obtained, frequently undergo stress MPI to evaluate underlying CAD. If no stress or rest abnormality of perfusion or function is observed, patients are typically

F i g u r e 2 . 1 3 â•… Resting sestamibi (MIBI)

injected during chest pain in emergency department (top) and 3 days post-PCI of the left circumflex coronary artery (LCX) (bottom) in a patient with no electrocardiogram or enzyme abnormalities. Clear evidence of extensive myocardial salvage in LCX territory is shown. Reproduced with permission from Ref. 83.

2 . 1 4 â•…Normal rest 201Tl single photon emission computed tomography (bottom) followed by adenosine 99m Tc-sestamibi (ADEN MIBI) (top) in a patient with intermittent chest pain, which had resolved prior to rest 201Tl injection. Reversible defects are seen in the left anterior descending and left circumflex territories. Angiography revealed 50% left main, 100% left anterior descending, 90% left circumflex, and 50% right coronary artery stenoses. Reproduced with permission from Ref. 82. Figure

32

discharged from the ED. Those with evidence of ischemia (Figure 2.14) or infarct are admitted.

jâ•…USE OF SPECT MP I IN SPECI FIC PAT IE NT POP U LAT I ONS WITH F REQUE NTLY ATYPI CAL CL I NICAL P RESENTAT ION S UGGEST IVE OF CAD A principal strength of nuclear cardiology is that large databases have been accumulated resulting in evidence documenting the effectiveness of SPECT MPI for risk stratification of appropriately selected patients with intermediate likelihood of CAD and/or unclear pretest clinical symptomatology. This evidence has resulted in several Class I indications for the use of stress SPECT MPI [10]. Due to the far fewer publications with PET, the guidelines, in general, have been confined to recommendations regarding SPECT; however, as noted above, they can be considered to also apply to PET MPI. Several specific lines of evidence are described below. 1. Evidence supporting nuclear imaging for patients with an intermediate risk or indeterminate treadmill test: Several reports support nuclear testing in patients with uninterpretable or intermediate exercise ECG response [10]. An initial report from Cedars-Sinai demonstrated that SPECT MPI was most effective in risk stratification and governing management of patients with Â�intermediate Duke treadmill score (DTS) [45]. Patients with a low DTS (hard-event rate ,1%) or high DTS (hard-event rate 7.7%) did not show further risk stratification with SPECT MPI. However, patients with an intermediate DTS, comprising the majority of patients studied, had an intermediate risk of hard events; patients with a normal SPECT MPI scan had very low event rates and were infrequently catheterized, those with moderately abnormal scans had intermediate rates of events and catheterization, and those with moderately to severely abnormal scans had higher rates of events and catheterization. Similar results were seen in subsequent multicenter studies reporting event rates and catheterization rates [10]. 2. Gender-based differences in the prognostic value of SPECT MPI: Female patients are often present with either atypical symptoms and usually stratified into lower risk categories despite presence of the significant CAD. Recent guidelines for cardiac imaging in women, taking into consideration these difficulties in the management of women with suspected CAD have been published by the AHA [46]. In women, due to breast tissue artifact, falsepositive SPECT MPI examinations are most notable in the anterior and anterolateral segments of the heart and are more common with Tl-201 than with the Tc-99m agents [47,48]. Improved accuracy has been reported with use of the Tc-99m agents as well with combined acquisition of gated EF and wall motion imaging, prone

Multimodality Imaging in Cardiovascular Medicine

imaging, and with the use of validated attenuation correction algorithms [48–51], with the resultant sensitivity and specificity being similar in women and men. â•…Regarding prognosis, pooled data including more than 7500 women noted annual rates of cardiac death or nonfatal MI of 0.4% for women with low risk or normal SPECT MPI [52]. High risk findings elevated a woman’s risk by nearly 10-fold with annual rates of major cardiac events of 6.3% for all women and 10.9% for diabetic subsets of women [52]. Separate criteria for abnormality have been recommended for ventricular function in women and men, resulting in similar prognostic content of combined perfusion and function information from gated SPECT in men and women [53]. â•…â•… Endothelial dysfunction and microvascular disease have been proposed as mechanisms for false-positive stress testing results in women, suggesting that some of these studies may represent true perfusion abnormalities without large vessel CAD. Recent evidence suggests that these SPECT MPI perfusion findings may be associated with increased near-term risk of major cardiac events [54], suggesting that prognostically important coronary disease states not involving obstructive CAD occur more frequently in women than in men, and that SPECT MPI could provide a tool for detection of this process. Due to the routine use of attenuation correction with PET, its application in women may be associated with reduced false positives due to breast attenuation. Combined prone and supine imaging with SPECT or attenuation correction with SPECT have also been shown to reduce the false-positive rate of SPECT MPI in women [14]. 3. Evidence supporting nuclear imaging for elderly patients: Another clinical subset population of patients with atypical symptomatology is that of elderly patients. With recent increased longevity of the population and the increasing prevalence of CAD as a function of age, large numbers of elderly patients are requiring diagnostic and/or prognostic assessment for CAD. The DTS, useful in many patient subsets, has been reported to be less effective in risk stratification of elderly patients [55]. The Mayo Clinic group reported that exercise SPECT MPI provides effective risk stratification in elderly men and elderly women. A cohort of 247 patients 75 years of age, patients undergoing Tl-201 SPECT MPI, was Â�followed for a median of 6.4 years for cardiac death. The summed stress score from SPECT MPI was significantly associated with cardiac death, but the DTS was not. The summed stress score from SPECT MPI classified 49% of patients as low risk and 35% of patients as high risk, with annual cardiac mortality rates of 0.8% and 5.8% respectively. Long proponents of the ETT alone as the initial test, the Mayo group concluded that if their results can be confirmed in future studies, exercise SPECT rather than ETT may emerge as the initial

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Atypical Chest Pain and Other Presentations

exercise testing modality in both women and men aged 75 years, even those who are able to exercise [55]. â•…Pharmacologic stress testing is increasingly being applied in the elderly who frequently are unable to exercise adequately and the elderly comprise a high proportion of patients undergoing pharmacologic stress imaging. For elderly patients as well as for those with functional limitations, similar risk assessment is possible with exercise and pharmacologic stress SPECT [29]. Consistent with data on other functionally impaired patients, the prognostic value of SPECT MPI is associated with higher cardiac event rates for normal to severely abnormal test results. These results were extended to dobutamine stress [56]. Recent evidence has shown a survival benefit with revascularization in elderly patients with extensive ischemia [56A]. 4. Evidence supporting MPI for African-American and other Ethnic Minority Patients: The rate of cardiac death or MI in African Americans with a normal SPECT MPI is approximately 2% per year, [10] likely a result of higher risk burden [54]. In a recent series, 2-year CV death or MI were compared in 1993 African American and 464 Hispanic patients as compared with 5258 Caucasian, non-Hispanics undergoing stress Tc-99m tetrofosmin SPECT MPI [32]. Moderateseverely abnormal SPECT MPI occurred more often in ethnic minority patients. The prognostic results noted a 1.4- to 1.6-fold and 2.3- to 5.6-fold higher risk of hard events in African American and Hispanic patients, respectively, with mild and moderate-severely abnormal SPECT MPI findings, (P , .0001 vs. Caucasians), apparently due to higher degree of comorbidity.

33

jâ•…ROLE OF CO RONA RY CT ANGI O GRAPHY I N EVAL UAT ION OF PATIE NTS W ITH ATYP ICAL CH EST PA IN CT Coronary Calcium Scanning Chronologically, noncontrast ECG-gated cardiac CT evolved before coronary CT angiography (CCTA) as the initial clinically relevant application of cardiac CT; it has enabled the accurate measurement of coronary artery calcification, opening up the opportunity for improved assessment of patients with subclinical coronary atherosclerosis. Coronary artery calcium (CAC) is thought to develop in the body’s attempt to contain and stabilize inflamed coronary plaque [57]. Coronary artery calcification is considered pathognomonic of coronary atherosclerosis. In general, evidence of CAC reflects a more advanced stage of plaque development. A quantitative relationship has been demonstrated between CAC and histopathologic evidence of coronary plaque area. Moreover, calcified plaque assessment correlates with pathologic assessment of the total amount of calcified plus noncalcified plaque [58]. As such, CAC serves as an indirect but proportional marker for global atherosclerotic burden. A large number of studies in tens of thousands of asymptomatic patients have consistently documented strong prognostic value of CAC scores. Estimators of risk with consideration of the CAC distribution by age, gender, and other clinical variables have been developed in order to further fine-tune the prediction of cardiac risk [59–61]. In this regard, a recent study reported distribution of the follow-up cardiac events by coronary calcium score (CCS) in 4 ethnic groups in the population of 6722 patients from

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F i g u r e 2 . 1 5 â•… Unadjusted Kaplan–Meier cumulative-event curves for coronary events among participants with coronary artery calcium scores of 0, 1 to 100, 101 to 300, and .300. Panel A shows the rates for major coronary events (myocardial infarction and death from coronary heart disease), and panel B shows the rates for any coronary event. The differences among all curves are statistically significant (P , .001). Reproduced with permission from Ref. 62.

3 4Multimodality Imaging in Cardiovascular Medicine

33 35

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>400 P = 0.87 F i g u r e 2 . 1 7 â•…Distribution of coronary artery calcium (CAC) scores for the 1119 patients manifesting a normal myocardial perfusion single100–400 photon emission computed tomography (MPS) (left) and the 76 patients P = 0.86 with an ischemic MPS (right). Reproduced with permission from Ref. 64. 1–100 P = 0.57

2 . 1 6 â•…Rates of incident coronary artery disease (CAD)/1000 person years at risk by joint categories of absolute Â�coronary artery calcium (CAC) group and age-sex-race/ethnicity–specific percentiles displays the rates of incident CAD/1000 person years at risk by joint categories of absolute CAC group and age-, sex-, and race/ ethnicity-Â�specific percentiles. Within a particular level of age-Â�specific, sexspecific, and race/ethnicity-specific percentile, there remains a clear trend of increasing risk across levels of the absolute CAC groups. In contrast, once absolute CAC category is fixed, there is no Â�increasing trend across levels of age-specific, sex-specific, and race/ethnicity-Â�specific categories. Reproduced with permission from Ref. 63. Figure

The Multi-Ethnic Study of Atherosclerosis (MESA) registry [62]. CAC was a significant predictor of both major cardiac events (cardiac death or MI) and any coronary events in overall population (Figure 2.15) as well as separately in all 4 ethnic groups in this study during a median follow-up of 3.9 years. Moreover, the new analysis of the data from the same registry [63] demonstrates that risk stratification based on standard absolute cutoff points of CAC (,100, 100–400 and .400 Agatston units) performed much better than agesex-race/ethnicity–specific percentiles in terms of model fit and discrimination (Figure 2.16). Recently, further analysis of the MESA data demonstrated that the CAC score significantly improved cardiac risk prediction over standard risk variables [61A]. That CAC and SPECT MPI measurements provide complementary information in assessing patients with suspected CAD has been shown in a large study from our lab compared to the frequency of ischemia on MPI with the magnitude of CAC abnormality in a total of 1195 patients without known coronary disease, who underwent both stress MPI and CAC tomography within 7.2 6 44.8 days [64]. Among the patients with a CAC ,100 in our study, MPI ischemia was rare, occurring in ,2% of such patients (Figure 2.17). As the CAC score increased in magnitude

above 100, the frequency of myocardial ischemia on MPI increased progressively. This study has brought up several important clinical considerations. First, it helped to define indications for stress MPI referral after CAC imaging. According to the results, a referral of patients for MPI is generally not needed when the CAC score is ,100 due to the very low likelihood of observing inducible myocardial ischemia in such patients. Conversely, when the CAC score is greater than 400, stress MPI (or other stress imaging modality, such as stress echocardiography or stress MRI) would appear to be generally beneficial, because the frequency of inducible ischemia is substantial within this CAC range, even in asymptomatic patients. Another aspect of our study was of particular importance in documenting the insensitivity of MPI for detecting coronary atherosclerosis (in contrast to detecting patients with hemodynamically significant CAD). Of 1119 patients with normal MPI, a large proportion had high enough CCS that there would be consensus that aggressive medical management is warranted: 56% had CCS .100 and 31% had CCS .400 (Figure 2.17). The wide range of CAC scores in the study population patients with normal MPI studies exposes an important limitation relevant to all forms of so-called “physiologic” stress imaging testing: they do not effectively screen for subclinical atherosclerosis. These findings suggest that if testing begins with MPS in a given patient, without known CAD further assessment of atherosclerotic burden by CAC testing in those with normal scans may be useful in assessment of the need for aggressive attempts to prevent coronary events (Figure 2.18). To date, however, there is little data to indicate that aggressive treatment of patients with subclinical atherosclerosis defined by CAC reduces subsequent cardiac events. In a randomized clinical trial, a part of the St Francis Heart Study showed a trend to less progression of the CCS in patients treated with statins versus a control group, but failed to reach

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A

B

F i g u r e 2 . 1 8 â•…Clinical case of the 67-year-old male patient, presenting with chronic atypical chest pain; past medical history is remarkable for hyperlipidemia. Initial stress-rest myocardial perfusion imaging demonstrated normal perfusion (A). Subsequent coronary computed tomography angiography (B), however, shows areas of extensive coronary calcifications of all 3 major epicardial coronary arteries (total calcium score 5 1212 Agatston units), and moderately obstructive disease (50%–69% range) of the mid LAD, and first diagonal and second diagonal branches. LAD, left anterior descending; LCX, left circumflex; RCA, right coronary artery; LM, left main.

statistical significance [65]. There is an increasing trend toward recommendation of CAC testing for asymptomatic at intermediate clinical risk, and for aggressive treatment of those with prognostically important amounts of CAC. As noted above, when the CAC score is .400, stress imaging for silent myocardial ischemia is now considered appropriate [66]. A recent study [67] has provided data supporting the approach that when such testing for ischemia is negative, the short-term cardiac event rates are low. In analysis of 1089 patients who had nonischemic exercise MPI after CAC testing, during a mean followup of 32 6 16 months, less than 1% underwent early

revascularization, and the annualized cardiac event rate was ,1% in all CAC subgroups, including those with CAC scores .1000. In summary, CAC measurements appear useful in patients with an intermediate clinical risk, when the need for aggressive preventive measures is not already clear. Currently there is increasing recommendations by prevention specialists that a CAC score of .100 defines a patient population deserving prevention therapy according to secondary prevention guidelines. There is consensus in the guidelines and appropriate use criteria that a score .400 defines a threshold above which merits prevention therapy

Multimodality Imaging in Cardiovascular Medicine

36

according to secondary prevention guidelines further testing for ischemia is considered appropriate. Importantly, however, in patients with atypical angina and other symptoms resulting in an intermediate likelihood of obstructive CAD, CAC scanning is not considered a sufficiently accurate test to rule out obstructive CAD as the cause of the symptoms. Patients may present with an obstructive noncalcified coronary plaque as being responsible for their first symptoms of CAD. In these patients, either ischemia testing, as discussed above, or CCTA would be more appropriate tests.

jâ•…C ORONA RY C T ANGI O GRAPHY: DI AGNOS TIC A ND PRO GNOS TIC IMPA CT I N DI FFERENT CLI NICAL POP ULAT IONS Although considered possible since the initial description by Hounsfield of computed tomography [68], the era of CCTA did not begin to grow significantly until 1998 when the first 4-slice multislice CT (MSCT) Â�scanners with rotation times of less than0.5 seconds became clinically available [69]. For practical purposes, the introduction of the 16-slice MSCT

scanners in 2001 marked the start of the rapid growth phase of CCTA [70]. This Â�development allowed routine visualization of even small coronary Â�segments, sparking a flame of interest from cardiologists and radiologists. Then in 2004, the introduction of 64-slice MSCT scanners resulted in a bonfire. By 2005, 4 major manufacturers were offering 64-slice scanners, providing CCTA with true 3D data in isotropic voxels of ∼0.5 mm and complete studies in 5 to10 heartbeats. In March 2005, a new society of cardiovascular CT (SCCT) was founded, and by July 2008, SCCT had over 4000 members, representing the most rapidly growing cardiac society on record. This modality has now begun to be applied in routine clinical practice; however, the extent to which it will be used in preference to stress imaging methods in patients with atypical angina or other symptoms indicating an intermediate likelihood of CAD has not yet been determined. Numerous studies of the diagnostic accuracy of the CCTA have been performed comparing CCTA to ICA. These studies have limitations such as referral bias discussed above for MPI, as well as limitations related to the use of ICA as a gold standard per se. The issues of referral bias are less prominent with CCTA than with MPI since nearly all of the correlative studies have been performed on patients already determined as needing ICA, in contrast to the MPI correlative studies in C

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F i g u r e 2 . 1 9 â•… Left panel: pooled estimates (18 studies; n 5 1286; 95% credible interval) for different levels of analysis. Left main artery: owing to numerical difficulties with the hierarchical summary receiver operating characteristic symmetric model, sensitivity (A) and specificity (B) were pooled using the weighted average method, and confidence intervals rather than credible intervals were reported. Right panel: Median (C) positive and (D) negative predictive values (PPV and NPV) across studies (range). CABG, coronary artery bypass graft; LAD, left anterior descending; LCX, left circumflex; RCA, right coronary artery. Reproduced with permission from Ref. 72.

Atypical Chest Pain and Other Presentations

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phy angiography (CCTA) per segmental analysis categorized by diameter stenoses on quantitative coronory angiography (QCA). In the graph, the diagnostic performance of CTCA is shown according to various diameter stenoses as measured by QCA in a per-segment analysis. The absolute number of segments per stenosis category is shown in the table. The highest frequencies of overestimated (FP) and underestimated (FN) coronary stenoses by CCTA were clustered around the cutoff value of 50% diameter reduction (significant coronary stenosis). FN, false negative; FP, false positive; TN, true negative; TP, true positive. Reproduced with permission from Ref. 73.

which the decision to perform ICA was frequently governed by the MPI test result itself. This new modality has been subjected to more assessments of sensitivity and specificity in patient groups being sent for invasive coronary angiography than any of the other noninvasive cardiac imaging modalities. On the basis of a large body of evidence, CCTA is considered the most accurate noninvasive test for the detection of CAD as defined by invasive coronary angiography. Meta-analyses of the sensitivity and specificity of CCTA have recently been published [71,72]. In one of these, pooled data from 18 CCTA studies were presented [72]; in this analysis, diagnostic performance of CCTA was found to be excellent (Figure 2.19). Recently, 3 large multicenter trials regarding the accuracy of CCTA for detecting CAD by ICA have been published. The most recent of these was a prospective, multicenter, multivendor study conducted with real-world analysis (no patients or segments were excluded because of impaired image quality attributable to either coronary motion or calcifications), involved 360 symptomatic patients with acute and stable anginal syndromes who were between 50 and 70 years of age and were referred for diagnostic conventional ICA, which was compared with CCTA [73]. In this population of patients with intermediate-to-high and high pretest likelihood of CAD, CCTA was reliable for ruling out significant CAD. Specificity of the CCTA in this study was lower than in most other reports, probably due to the inclusion of all segments and patients despite observed artifacts. An important observation from this study is presented in Figure 2.20; the

AUC (95% C.I.) = 0.95 (0.92, 0.97)

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characteristic curve for identification of patients by coronary computed tomographic angiography (CCTA) with .70% coronary artery stenosis by quantitative coronary angiography. The points on the plot represent the 6 categories of interpretation for CCTA used in this study: 0 5 100% stenosis; 1 5 70% to 99% stenosis; 2 5 50% to 69% stenosis; 3 5 30% to 49% stenosis; 4 5 , 30% stenosis; and 5 5 no stenosis. The ROC shows the degree of the CAD . 70% stenosis prediction by invasive angiography. AUC 5 area under the receiver-operating characteristic curve; CI 5 confidence interval. Bottom: diagnostic performance of the CCTA (per-patient analysis). Reproduced with permission from Ref. 74.

majority of the false-positive and false-negative studies were clustered around the cutoff of the 50% luminal stenosis. Another important recently published prospective multicenter trial (ACCURACY; Assessment by Coronary Computed Tomographic Angiography of Individuals Undergoing Invasive Coronary Angiography) [74] investigated 230 symptomatic patients with intermediate-to high and high likelihood of CAD who were referred for the ICA; in this study, 64-slice CCTA showed high diagnostic accuracy for detection of obstructive coronary stenosis at both thresholds of 50% and 70% stenosis (Figure 2.21). The authors also concluded that the 99% negative predictive value at the patient and vessel level observed in this study, establishes CCTA as an effective noninvasive alternative to ICA to rule out obstructive CAD. In this study, the prevalence of greater than 50% stenosis was 25%. Similar high diagnostic accuracy of the CCTA compared to ICA was demonstrated in CACTUS (Coronary Angiography by Computed Tomography with the use of a submillimeter resolution) trial [75], which included 243 patients with an intermediate pretest probability for CAD. In a subsequent multicenter trial, The CORE 64 (The Coronary Artery Evaluation using 64-Row Multidetector Computed Tomography Angiography) study, the overall accuracy was similar, but with somewhat lower negative predictive value [76]. However, this difference is most likely attributed to the manner in which lesions were assessed in the presence of coronary artery calcification that may obscure the coronary lumen as well as to differences in prevalence of obstructive CAD in the various studies. In CORE 64 the prevalence of greater than 50% stenosis was 56%.

38

F i g u r e 2 . 2 2 â•… Clinical case of a 42-year-old male patient presenting with shortness of breath and atypical chest pain. Risk factors: smoking family Hx of early coronary artery disease (CAD) his resting electrocardiogram was normal. Coronary computed tomography angiography (shown) was normal, ruling out CAD as a reason for the patient’s symptoms. LAD, left anterior descending; LCX, left circumflex; RCA, right coronary artery.

F i g u r e 2 . 2 3 â•… High degree stenosis of the proximal right coronary

artery on coronary computed tomography angiography (A) of the 50-year-old female patient presenting with shortness of breath and chest pain; severity and location of the lesion were confirmed on the invasive coronary angiogram (B).

In patients with an intermediate likelihood of CAD, the clinical implications of a normal CCTA study are Â�generally clear; the high negative predictive value implies that the symptoms leading to testing are very unlikely to be due to obstructive CAD (Figure 2.22). The Â�clinical Â�implications of the abnormal CCTA study are often, Â�however, less clear. Although the coronary angiographic correlations have been excellent (Figure 2.23), the Â�correlations between CCTA and functional measures of ischemia have been much lower. In the studies to date in which both SPECT MPI and CCTA have been Â�performed, less than 50% of the patients with CCTA studies showing .50% stenosis demonstrated ischemia by SPECT MPI (Figure 2.24) [77]. Since a stenosis of 70% severity is now more widely required as an angiographic criterion for the need for revascularization, it would be of interest to see the relationship between CCTA and ischemia using this angiographic cut-point. However, given the lack of excellent correlation even between invasive angiographic stenosis and fractional flow reserve, the current gold standard for hemodynamic significance [78,79],

Multimodality Imaging in Cardiovascular Medicine

it is likely that a large proportion of such lesions, even with the 70% stenosis criterion, will not demonstrate ischemia. CCTA is a new modality in the armamentarium of the advanced cardiac imaging. Thus, prognostic data available still cover either relatively small populations or provides a limited (either short-term or midterm) follow-up length. Nevertheless, initial publications in this field demonstrate powerful predictive value of CCTA, with excellent prognosis in those patients who have no evidence of atherosclerosis on their index scan [9,80]. Recently, more detailed analysis of a larger population (n 5 1127) has shown that in patients with chest pain, CCTA identifies increased risk for all-cause death [81]. In this population, a negative CCTA was associated with extremely low all-cause mortality. Notably, the CCTA predictors of death included proximal LAD stenosis and number of vessels with .50% and .70% stenosis. Of importance, there was an appropriate increase in the death rate associated with each step of increased jeopardy when the CCTA was assessed by the Duke Prognostic CAD Index (Figure 2.25). A significant additive prognostic value of the combined CCTA and MPI results is also of importance; in a recent communication in this field, presence of both abnormal CTA and MPI carried a substantially worse prognosis than any on these tests alone (Figure 2.26) [82]. In this European study, 541 patients who had both MPI and CCTA, were followed up for a median of 672 days; hard event rate in patients with none or mild CAD as defined by CCTA (,50% stenosis), was 1.8% per year versus 4.8% per year in patients with significant CAD (50% stenosis). A normal MPI (SSS , 4) and abnormal MPI (SSS  4) were associated with an event rate of 1.1% and 3.8% per year, respectively. CCTA and MPI findings were associated with synergistic prognostic impact, and their combined utilization resulted in significantly improved prediction of cardiac events (P , .005) [82].

F i g u r e 2 . 2 4 â•… Available to-date studies demonstrating positive and negative predictive values of the coronary computed tomography angiography (CCTA) stenosis .50% in predicting myocardial perfusion imaging ischemia. Reproduced with permission from Ref. 77.

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None or Mild (<50%) Plaque (n = 422) ≥2 Mild (30%–42%) Plaque with Predmal Plaque in 1 Artery (n = 64), P = 0.192 1 Moderate (50%–69%) Plaque (n = 212), P = 0.055 2 Moderate (50%–69%) Plaque or 1 Severe (≥210%) Plaque (n = 101), P = 0.013

Cumulative Survival

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F i g u r e 2 . 2 5 â•… Cumulative survival in patients exhibiting plaque by the Duke Prognostic Coronary Artery Disease Index. Risk-adjusted P , .001 (controlling for age, family history, and dyslipidemia). LAD, left anterior descending artery. Reproduced with permission from Ref. 81.

F i g u r e 2 . 2 6 â•… Kaplan-Meier Curves for hard cardiac events in patients with a normal or abnormal myocardial perfusion imaging (MPI) and with

or without coronary artery disease (CAD) on multislice computed tomography (MSCT) angiography. Survival curves for hard events (all-cause mortality and nonfatal infarction) in patients with a normal MPI (SSS , 4) and none or mild CAD (,50% stenosis) on MSCT, in patients with an abnormal MPI (SSS  4) and with none or mild CAD (,50% stenosis) on MSCT, in patients with a normal MPI (SSS , 4) and significant CAD (MSCT  50% stenosis), and finally, in patients with an abnormal MPI (SSS  4) and significant CAD (MSCT  50% stenosis). Reproduced with permission from Ref. 82.

jâ•…D ETE CTION AND MANAGEMENT OF CAD I N PATIENTS WI TH CHEST PA IN S YNDROMES: APP ROACH TO INTEGR ATED US E OF CORONA RY CAL CIUM SCO RE, C TA, AND MPI In a symptomatic patient, the first question that arises is what the cause of the symptoms is: that is, establishing the Â�diagnosis. For risk assessment, the short-term as well as the long-term risk needs to be considered, in order to appropriately guide the management decisions, which chiefly deal with whether revascularization needs to be considered [83] and what degree of intensity of medical therapy is warranted. In the symptomatic patients without limiting symptoms, the pretest likelihood of angiographically significant CAD becomes the starting point for the clinician—rather than the 10-year risk used in

asymptomatic patients. This likelihood is assessed, employing age, gender, risk factors, and symptoms, as initially suggested by Diamond et al [4,6]. We have adopted the cut-points 15% and 85% based on our prognostic observations, resulting in 3 likelihood groups: low (,15%), intermediate (15–85%) and high (.85%). In general, patients with new or limiting angina go straight to selective coronary angiography. At the other end of the likelihood spectrum, symptomatic patients with a low likelihood of CAD (,15%), generally require only primary prevention and no testing, similar to asymptomatic patients with a low 10-year risk. This might apply, for example, to a 30 year old with no risk factors for CAD experiencing nonanginal chest discomfort. Since Bayesian theory has shown that the value of noninvasive diagnostic testing is greatest in patients with an intermediate likelihood of disease, patients with an intermediate

4 0Multimodality Imaging in Cardiovascular Medicine

Algorithm for Sequential Use to Non-Invasive Imaging in Pts with Intermediate Pretest Lk of CAD

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Algorithm for Sequential Use to Non-Invasive Imaging in Pts with Intermediate Pretest Lk of CAD

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F i g u r e 2 . 2 7 â•… CCTA approach to diagnosis and management of

coronary artery disease in symptomatic patients (pts) with an intermediate pretest likelihood of CAD. Abnl, abnormal; revasc, revascularization. CCTA, coronary computed tomography angiography; CAD, coronary artery disease. Reproduced with permission from Ref. 84.

likelihood of CAD (15–85%) become excellent candidates for diagnostic testing. Although stress techniques have generally been used in these patients, CCTA may become the preferred initial test in this group of patients, particularly in those with lower pretest likelihood of CAD. An approach to the symptomatic patient with an intermediate pretest likelihood of CAD, based on using CCTA as the initial test is shown in Figure 2.27 [84]. After the CCTA, the need for further testing and therapy is guided by the post-test likelihood of CAD and the extent and severity of the observed disease. If the CCTA is normal (no stenosis, no coronary calcium), primary prevention would be appropriate. It is likely that the very high negative predictive value—the definitive ability to rule out CAD will become a principal driving force in the initial application of CCTA. On the other hand, if critical proximal stenoses are observed (eg, .90%), direct referral to selective coronary angiography would appear to be appropriate. It must be recognized that currently CCTA is almost purely anatomic in its information. Although providing important information for guiding medical management and establishing diagnosis, it is limited in the information regarding need for revascularization. Thus, if a coronary stenosis is defined by CCTA but the anatomy is not compelling regarding the need for revascularization, referral for stress ischemia testing (eg, MPI) would appear appropriate to determine the need to consider coronary revascularization. The concept that additional testing for ischemia might be needed following CCTA raises the problem of layering of testing—a situation in which a new test (CCTA) simply adds another layer, and the established test (MPI) still needs to be performed. Although this combined testing is needed in some cases, there are ways in which the frequency of its use can be reduced. One of these ways is to interpret the CCTA with a spectrum of findings rather

>10% ischemia or 5-10% ischemia + ancillary risk market

CCTA

Functional imaging No ischemia

5-10% ischemia No ancillary risk marker

Equivocal/dicordant

Normal*

No compelling anatomy Safe discharge (1° prevention)

Compelling anatomy

Medical therapy & aggressive risk factor modification (2° prevention)

ICA + poss revasc

F i g u r e 2 . 2 8 â•… MPI approach to diagnosis and management of CAD in symptomatic patients (pts) with an intermediate pretest likelihood of CAD. Ancillary markers of high risk are those listed in Table 2.1. *With normal MPI in patients not already identified as requiring maximal medical therapy using secondary prevention guidelines, consider atherosclerosis imaging. CAD, coronary artery disease; ICA, invasive coronary angiography; CCS, coronary calcium scan. Reproduced with permission from Ref. 84.

than a binary normal and abnormal approach based on a % stenosis cut-point. In this regard, a recent manuscript [85] has shown that a graded classification of results of CCTA can reduce the need for additional testing to rule out angiographically significant CAD. With this system, if lesions by CCTA are seen to show less than 50% diameter narrowing, an angiographic lesion of greater than 70% is highly unlikely. If a lesion is considered to show 70% narrowing, ICA is unlikely to show ,50% stenosis. The lesions that remain in the clearly borderline group regarding the likelihood of ICA stenosis are those in the 50% to 69% narrowing group. An alternate approach in this intermediate likelihood group would be to perform ischemia testing with MPI as the initial test with consideration of CCTA when the results of MPI are uncertain (Figure 2.28). With this approach, patients with extensive ischemia would be referred to ICA. Patients with 5% to 10% ischemia would be further assessed for the presence of ancillary high risk markers (low EF, transient ischemic dilation, and so on; Table 2.2) or high risk conditions (advanced age, diabetes mellitus, atrial fibrillation, pharmacologic stress, and dyspnea). Those with one or more of these high risk markers or conditions could be candidates for ICA. In those with 5% to 10% ischemia and none of the high risk markers or conditions, consideration is given to the performance of CCTA. CCTA is also considered in patients with equivocal MPI or in whom the MPI results and the results of stress testing are markedly discordant (eg, severe ST depression with a normal MPI study). The reason for suggesting the use of CCTA in these patients is that a small percentage of patients with left main CAD might be missed by MPI in the absence of absolute flow measurements [28] (Figure 2.5).

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Atypical Chest Pain and Other Presentations41

F i g u r e 2 . 2 9 â•… MPI approach to diagnosis in management of CAD in

symptomatic patients with the intermediate pre test likelihood of CAD in circumstances where CCTA is not available or contraindicated. *ICA should also be considered in patients with less extensive atherosclerosis. When one or more ancillary high risk markers are present (see Table 2.2).

Another group in which CTA might be commonly employed is in patients with equivocal nuclear results or with a marked discordance in the clinical or ECG results and the nuclear results. Usefulness of CTA in patients with equivocal or nondiagnostic MPI was most recently demonstrated by Abidov et al [86]. The approach to the patient changes somewhat if facilities and /or expertise for CCTA are not available or CCTA is contraindicated (e.g., allergy to contrast, renal failure) or can not be accurately performed (e.g., atrial fibrulation) (Figure 2.29). In these circumstances, symptomatic patients with an intermediate likelihood of CAD or known CAD are candidates for SPECT or PET MPI. The widely available assessment of CCS can then be of further help in these patients in situations where MPI results are normal, equivocal, or discordant with clinical stress test results. Hybrid systems are now available allowing the combined assessments of anatomy and function [88,89]. Both PET and SPECT are intrinsically techniques without high Â�spatial resolution. Recently, PET/CT has become the Â�standard for almost all commercially available PET machines, linking the high resolution of CT with the functional richness of PET. SPECT/CT systems are now available from multiple Â�manufacturers. In the future, it is possible that SPECT systems with Â�dramatic increases in sensitivity as well as increases in spatial Â�resolution could become available, with the potential of rapid, dynamic SPECT and routine absolute quantifications of coronary flow. In some form, it is predicted that hybrid systems will play an increasingly important role for combined anatomic/functional imaging in the future. Of practical clinical relevance, these systems make it possible to combine testing of myocardial ischemia with assessment of coronary atherosclerosis

through the performance of a coronary calcium scan with CT of the hybrid device at the time that attenuation correction scanning is performed with either PET/CT or SPECT/ CT. At Cedars-Sinai Medical Center, we routinely provide a CCS with reports of PET MPI, and, anecdotally have found great value in this combination, as suggested by our previous work [64]. Which of the approaches described in this chapter is optimal has yet to be determined. A large randomized clinical trial. The PROMISE Trial (Prospective Multicenter Imaging Study for Evaluation of Chest Pain) is currently being conducted by the National Lung, Heart, and Blood Institute. The study proposes to enroll 10,000 patients with symptoms suspicious for significant coronary artery disease requiring non emergent non invasive testing to be randomized to an anatomic strategy involving 64 slice coronary CT angiography versus a functional strategy employing stress testing with either exercise ECG, stress echo, or stress myocardial perfusion imaging. The patients will be followed for 30 months for complications of death, myocardial infarction, or unstable angina. The study will also be evaluated for comparative radiation exposure cost and quality of life. The study is designed with a coronary CT angiography superiority hypothesis, but also will be considered positive if a non inferiority endpoint is reached. Additional study will be needed to compare CCTA to the combination of MPI with evaluation of subclinical coronary atherosclerosis as can be provided routinely by the use of the hybrid PET/CT or SPECT/CT systems.

jâ•… FU T URE CO NSI DERATIONS Perhaps the greatest future potential of the discipline of nuclear cardiology lies in molecular imaging, due to the ability of the radiotracer technique to assess minute tracer concentrations of critical importance for this field. SPECT and PET methods are thousands of times more sensitive than ultrasound, MRI, or CT methods. Already, provocative information of the power of this approach has been demonstrated in assessing the activity of atherosclerotic disease. In the carotid arteries, for example, F-18 FDG PET has been studied for imaging plaque inflammation and Tc-99m annexin SPECT has been evaluated for imaging apoptosis within plaque—both accepted markers of plaque instability. Quite possibly, nuclear techniques may actually hold the key to one of the most elusive goals of imaging in CAD—that of detecting the vulnerable coronary plaque in need of aggressive intervention [90]. Another example of molecular imaging in patients with chest pain might be the use of beta-methyl-iodophenyl-pentadecanoic acid (BMIPP) [91]. This agent has been shown to reveal persistent metabolic abnormalities for greater than 24 hours after transient myocardial ischemia. A possible clinical

42Multimodality Imaging in Cardiovascular Medicine

application of BMIPP would be the assessment of patients presenting several hours to days after a possible severe ischemic episode, potentially providing direct evidence of the recent severe ischemia at a time when perfusion had returned to normal. Given the recent emergence of CCTA as an effective noninvasive procedure for CAD detection, it is likely that the growth rate of MPT will be reduced over the next several years from the double-digit annual growth that has been experienced for nearly 20 years. At the same time, the need for MPI in patients with equivocal CCTA studies, and the increased number of patients with known CAD in whom CCTA is not currently effective, is likely to keep the numbers of nuclear MPI studies in a similar range in what is being performed at this time. In the patients with known CAD, MPI approaches are likely to remain cost effective for identification of which of these patients are most likely to benefit from medical therapy versus coronary revascularization or myocardial reshaping procedures.

jâ•… ACKNOWLEDG MENT The authors thank Xingping Kang, MD for her expert assistance in preparation of the manuscript and illustrative materials for this chapter.

jâ•…REFERENC ES â•‡ 1. Rosamond W, Flegal K, Furie K, et al. Heart disease and stroke Â�statistics—2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2008;117:e25–e146. â•‡ 2. National Center for Health Statistics. Compressed Mortality File: Underlying Cause of Death, 1999 to 2005. Centers for Disease Control and Prevention. â•‡ 3. Gibbons RJ, Abrams J, Chatterjee K, et al. ACC/AHA 2002 guideline update for the management of patients with chronic stable angina— summary article: a report of the American College of Cardiology/ American Heart Association Task Force on practice guidelines (Committee on the management of patients with chronic stable angina). J Am Coll Cardiol. 2003;41:159–168. â•‡ 4. Diamond GA, Staniloff HM, Forrester JS, Pollock BH, Swan HJ. Computer-assisted diagnosis in the noninvasive evaluation of patients with suspected coronary artery disease. J Am Coll Cardiol. 1983;1:444–455. â•‡ 5. Abidov A, Rozanski A, Hachamovitch R, et al. Prognostic significance of dyspnea in patients referred for cardiac stress testing. N Engl J Med. 2005;353:1889–1898. â•‡ 6. Diamond GA, Forrester JS. Analysis of probability as an aid in the clinical diagnosis of coronary-artery disease. N Engl J Med. 1979;300:1350–1358. â•‡ 7. Chaitman BR, Bourassa MG, Davis K, et al. Angiographic prevalence of high-risk coronary artery disease in patient subsets (CASS). Circulation. 1981;64:360–367. â•‡ 8. Diamond GA, Denton TA, Berman DS, Cohen I. Prior restraint: a Bayesian perspective on the optimization of technology utilization for diagnosis of coronary artery disease. Am J Cardiol. 1995;76:82–86.

â•‡ 9. Gaemperli O, Valenta I, Schepis T, et al. Coronary 64-slice CT angiography predicts outcome in patients with known or suspected coronary artery disease. Eur Radiol. 2008;18:1162–1173. 10. Klocke FJ, Baird MG, Lorell BH, et al. ACC/AHA/ASNC guidelines for the clinical use of cardiac radionuclide imaging—Â�executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/ AHA/ASNC Committee to Revise the 1995 Guidelines for the Clinical Use of Cardiac Radionuclide Imaging). J Am Coll Cardiol. 2003;42:1318–1333. 11. Gibbons RJ, Abrams J, Chatterjee K, et al. ACC/AHA 2002 guideline update for the management of patients with chronic stable angina— summary article: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines (Committee on the management of patients with chronic stable angina). Circulation. 2003;107:149–158. 12. Taillefer R, DePuey EG, Udelson JE, Beller GA, Latour Y, Reeves F. Comparative diagnostic accuracy of Tl-201 and T c-99m sestamibi SPECT imaging (perfusion and ECG-gated SPECT) in detecting coronary artery disease in women. J Am Coll Cardiol. 1997;29:69–77. 13. Nishina H, Slomka PJ, Abidov A, et al. Combined supine and prone quantitative myocardial perfusion SPECT: method development and clinical validation in patients with no known coronary artery disease. J Nucl Med. 2006;47:51–58. 14. Slomka PJ, Nishina H, Abidov A, et al. Combined quantitative supine-prone myocardial perfusion SPECT improves detection of coronary artery disease and normalcy rates in women. J Nucl Cardiol. 2007;14:44–52. 15. Heller GV, Bateman TM, Johnson LL, et al. Clinical value of attenuation correction in stress-only Tc-99m sestamibi SPECT imaging. J Nucl Cardiol. 2004;11:273–281. 16. Nandalur KR, Dwamena BA, Choudhri AF, et al. Diagnostic performance of positron emission tomography in the detection of coronary artery disease: a meta-analysis. Academic Radiology. 2008;15: 444–451. 17. Bateman TM, Heller GV, McGhie AI, et al. Diagnostic accuracy of rest/stress ECG-gated Rb-82 myocardial perfusion PET: comparison with ECG-gated Tc-99m sestamibi SPECT. J Nucl Cardiol. 2006;13:24–33. 18. Hachamovitch R, Hayes SW, Friedman JD, Cohen I, Berman DS. Comparison of the short-term survival benefit associated with revascularization compared with medical therapy in patients with no prior coronary artery disease undergoing stress myocardial perfusion single photon emission computed tomography. Circulation. 2003;107:2900–2907. 19. Rozanski A, Diamond GA, Berman D, Forrester JS, Morris D, Swan HJ. The declining specificity of exercise radionuclide Â�ventriculography. N Engl J Med. 1983;309:518–522. 20. Hachamovitch R, Shaw L, Berman DS. Methodological considerations in the assessment of noninvasive testing using outcomes research: pitfalls and limitations. Prog Cardiovasc Dis. 2000;43:215–230. 21. Gibbons RJ, Chatterjee K, Daley J, et al. ACC/AHA/ACP-ASIM guidelines for the management of patients with chronic stable angina: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on management of patients with chronic stable angina). J Am Coll Cardiol. 1999;33:2092–2197. 22. Gibbons RJ, Hodge DO, Berman DS, et al. Long-term outcome of patients with intermediate-risk exercise electrocardiograms who do not have myocardial perfusion defects on radionuclide imaging. Circulation. 1999;100:2140–2145. 23. Yusuf S, Zucker D, Peduzzi P, et al. Effect of coronary artery bypass graft surgery on survival: overview of 10-year results from randomised trials by the Coronary Artery Bypass Graft Surgery Trialists Collaboration [see comments] [published erratum appears in Lancet 1994 November 19;344(8934):1446]. Lancet. 1994;344:563–570. 24. Ladenheim ML, Kotler TS, Pollock BH, Berman DS, Diamond GA. Incremental prognostic power of clinical history, exercise

C H A P TER 2

•

Atypical Chest Pain and Other Presentations

electrocardiography and myocardial perfusion scintigraphy in suspected coronary artery disease. Am J Cardiol. 1987;59:270–277. 25. Shaw LJ, Hendel R, Borges-Neto S, et al. Prognostic value of normal exercise and adenosine (99m)Tc-tetrofosmin SPECT imaging: results from the multicenter registry of 4728 patients. J Nucl Med. 2003;44:134–139. 26. Hachamovitch R, Hayes SW, Friedman JD, et al. Determinants of risk and its temporal variation in Patients with normal stress myocardial perfusion scans. What is the warranty period of a normal scan? J Am Coll Cardiol. 2003;41:1329–1340. 27. Abidov A, Bax JJ, Hayes SW, et al. Transient ischemic dilation ratio of the left ventricle is a significant predictor of future cardiac events in patients with otherwise normal myocardial perfusion SPECT. J Am Coll Cardiol. 2003;42:1818–1825. 28. Berman DS, Kang X, Slomka PJ, et al. Underestimation of extent of ischemia by gated SPECT myocardial perfusion imaging in patients with left main coronary artery disease. J Nucl Cardiol. 2007;14:521–528. 29. Hachamovitch R, Berman DS, Shaw LJ, et al. Incremental prognostic value of myocardial perfusion single photon emission computed tomography for the prediction of cardiac death: differential stratification for risk of cardiac death and myocardial infarction. Circulation. 1998;97:535–543. 30. Berman DS, Abidov A, Kang X, et al. Prognostic validation of a 17-segment score derived from a 20-segment score for myocardial perfusion SPECT interpretation. J Nucl Cardiol. 2004;11:414–423. 31. Ladenheim ML, Pollock BH, Rozanski A, et al. Extent and severity of myocardial hypoperfusion as predictors of prognosis in patients with suspected coronary artery disease. J Am Coll Cardiol. 1986;7:464–471. 32. Shaw LJ, Hendel RC, Cerquiera M, et al. Ethnic differences in the prognostic value of stress technetium-99m tetrofosmin gated singlephoton emission computed tomography myocardial perfusion imaging. J Am Coll Cardiol. 2005;45:1494–1504. 33. Hachamovitch R, Berman DS. The use of nuclear cardiology in clinical decision making. Semin Nucl Med. 2005;35:62–72. 34. Berman DS, Kang X, Hayes SW, et al. Adenosine myocardial perfusion single-photon emission computed tomography in women compared with men. Impact of diabetes mellitus on incremental prognostic value and effect on patient management. J Am Coll Cardiol. 2003;41:1125–1133. 35. Abidov A, Hachamovitch R, Rozanski A, et al. Prognostic implications of atrial fibrillation in patients undergoing myocardial perfusion single-photon emission computed tomography. J Am Coll Cardiol. 2004;44:1062–1070. 36. Marwick TH. Dyspnea and risk in suspected coronary disease. N Engl J Med. 2005;353:1963–1965. 37. Hansen CL, Goldstein RA, Akinboboye OO, et al. Myocardial perfusion and function: single photon emission computed tomography. J Nucl Cardiol. 2007;14:e39–e60. 38. Hachamovitch R, Rozanski A, Hayes SW, et al. Predicting therapeutic benefit from myocardial revascularization procedures: are measurements of both resting left ventricular ejection fraction and stress-induced myocardial ischemia necessary? J Nucl Cardiol. 2006;13:768–778. 39. Berman DS, Hachamovitch R, Kiat H, et al. Incremental value of prognostic testing in patients with known or suspected ischemic heart disease: a basis for optimal utilization of exercise technetium99m sestamibi myocardial perfusion single-photon emission computed tomography. J Am Coll Cardiol. 1995;26:639–647. 40. Shaw LJ, Heller GV, Travin MI, et al. Cost analysis of diagnostic testing for coronary artery disease in women with stable chest pain. Economics of Noninvasive Diagnosis (END) Study Group. J Nucl Cardiol. 1999;6:559–569. 41. Shaw LJ, Hachamovitch R, Berman DS, et al. The economic consequences of available diagnostic and prognostic strategies for the evaluation of stable angina patients: an observational assessment of the value of precatheterization ischemia. Economics of Noninvasive Diagnosis (END) Multicenter Study Group. J Am Coll Cardiol. 1999;33:661–669.

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42. Boden WE, O’Rourke RA, Teo KK, et al. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med. 2007;356:1503–1516. 43. Shaw LJ, Berman DS, Maron DJ, et al. Optimal medical therapy with or without percutaneous coronary intervention to reduce ischemic burden: results from the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial nuclear substudy. Circulation. 2008;117:1283–1291. 44. Udelson JE, Beshansky JR, Ballin DS, et al. Myocardial perfusion imaging for evaluation and triage of patients with suspected acute cardiac ischemia: a randomized controlled trial. JAMA. 2002;288:2693–2700. 45. Hachamovitch R, Berman DS, Kiat H, et al. Exercise myocardial perfusion SPECT in patients without known coronary artery disease: incremental prognostic value and use in risk stratification. Circulation. 1996;93:905–914. 46. Mieres JH, Shaw LJ, Arai A, et al. Role of noninvasive testing in the clinical evaluation of women with suspected coronary artery disease: Consensus statement from the Cardiac Imaging Committee, Council on Clinical Cardiology, and the Cardiovascular Imaging and Intervention Committee, Council on Cardiovascular Radiology and Intervention, American Heart Association. Circulation. 2005;111:682–696. 47. Shaw LJ, Hachamovitch R, Redberg RF. Current evidence on diagnostic testing in women with suspected coronary artery disease: choosing the appropriate test. Cardiol Rev. 2000;8:65–74. 48. Mieres JH, Shaw LJ. Stress myocardial perfusion imaging in the diagnosis and prognosis of women with suspected coronary artery disease. Cardiol Rev. 2003;11:330–336. 49. Mieres JH, Udelson JE. Meta-analysis of exercise testing to detect coronary artery disease in women. Am J Cardiol. 1999;84:1454–1456. 50. Makaryus AN, Shaw LJ, Mieres JH. Diagnostic strategies for heart disease in women: an update on imaging techniques for optimal management. Cardiol Rev. 2007;15:279–287. 51. Slomka PJ, Fish MB, Lorenzo S, et al. Simplified normal limits and automated quantitative assessment for attenuation-corrected myocardial perfusion SPECT. J Nucl Cardiol. 2006;13:642–651. 52. Shaw LJ, Iskandrian AE. Prognostic value of gated myocardial perfusion SPECT. J Nucl Cardiol. 2004;11:171–185. 53. Sharir T, Kang X, Germano G, et al. Prognostic value of poststress left ventricular volume and ejection fraction by gated myocardial perfusion SPECT in women and men: gender-related differences in normal limits and outcomes. J Nucl Cardiol. 2006;13:495–506. 54. Shaw LJ, Bairey Merz CN, Pepine CJ, et al. Insights from the NHLBISponsored Women’s Ischemia Syndrome Evaluation (WISE) Study: Part I: gender differences in traditional and novel risk factors, symptom evaluation, and gender-optimized diagnostic strategies. J Am Coll Cardiol. 2006;47:S4–S20. 55. Valeti US, Miller TD, Hodge DO, Gibbons RJ. Exercise single-photon emission computed tomography provides effective risk stratification of elderly men and elderly women. Circulation. 2005;111:1771–1776. 56. Schinkel AF, Elhendy A, Biagini E, et al. Prognostic stratification using dobutamine stress 99mTc-tetrofosmin myocardial perfusion SPECT in elderly patients unable to perform exercise testing. J Nucl Med. 2005;46:12–18. 56A.â•‡ Hachamovitch R, Kang X, Amanullah AM, Abidov A, Hayes S, Friedman JD, et al. Prognostic implications of myocardial perfusion single-photon emission computed tomography in the elderly. Circulation 2009;120:2197–21206. 57. Giri J, McDermott MM, Greenland P, et al. Statin use and functional decline in patients with and without peripheral arterial disease. J Am Coll Cardiol. 2006;47:998–1004. 58. Rumberger JA, Simons DB, Fitzpatrick LA, Sheedy PF, Schwartz RS. Coronary artery calcium area by electron-beam computed tomography and coronary atherosclerotic plaque area. A histopathologic correlative study. Circulation. 1995;92:2157–162. 59. Greenland P, Bonow RO, Brundage BH, et al. ACCF/AHA 2007 clinical expert consensus document on coronary artery calcium scoring by

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computed tomography in global cardiovascular risk assessment and in evaluation of patients with chest pain: a report of the American College of Cardiology Foundation Clinical Expert Consensus Task Force (ACCF/AHA Writing Committee to Update the 2000 Expert Consensus Document on Electron Beam Computed Tomography) developed in collaboration with the Society of Atherosclerosis Imaging and Prevention and the Society of Cardiovascular Computed Tomography. J Am Coll Cardiol. 2007;49:378–402. 60. Budoff MJ, Achenbach S, Blumenthal RS, et al. Assessment of coronary artery disease by cardiac computed tomography: a scientific statement from the American Heart Association Committee on Cardiovascular Imaging and Intervention, Council on Cardiovascular Radiology and Intervention, and Committee on Cardiac Imaging, Council on Clinical Cardiology. Circulation. 2006;114:1761–1791. 61. Yan LL, Liu K, Daviglus ML, et al. Education, 15-year risk factor progression, and coronary artery calcium in young adulthood and early middle age: the Coronary Artery Risk Development in Young Adults study. JAMA. 2006;295:1793–1800. 61A.â•‡ Polonsky TS, McClelland RL, Jorgensen NW, Bild DE, Burke GL, Guerci AD, et al. Coronary artery calcium score and risk classification for coronary heart disease prediction. JAMA;303:1610–1616. 62. Detrano R, Guerci AD, Carr JJ, et al. Coronary calcium as a predictor of coronary events in four racial or ethnic groups. N Engl J Med. 2008;358:1336–1345. 63. Budoff MJ, Nasir K, McClelland RL, et al. Coronary calcium predicts events better with absolute calcium scores than age-sex-race/ethnicity percentiles: MESA (Multi-Ethnic Study of Atherosclerosis). J Am Coll Cardiol. 2009;53:345–352. 64. Berman DS, Wong ND, Gransar H, et al. Relationship between stressinduced myocardial ischemia and atherosclerosis measured by coronary calcium tomography. J Am Coll Cardiol. 2004;44:923–930. 65. Arad Y, Goodman KJ, Roth M, Newstein D, Guerci AD. Coronary calcification, coronary disease risk factors, C-reactive protein, and atherosclerotic cardiovascular disease events: the St. Francis Heart Study. J Am Coll Cardiol. 2005;46:158–165. 66. Hendel RC, Budoff MJ, Cardella JF, et al. ACC/AHA/ACR/ASE/ASNC/ HRS/NASCI/RSNA/SAIP/SCAI/ SCCT/SCMR/SIR 2008 Key data elements and definitions for cardiac imaging: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Data Standards (Writing Committee to Develop Clinical Data Standards for Cardiac Imaging). Circulation. 2009;119:154–186. 67. Rozanski A, Gransar H, Wong ND, et al. Clinical outcomes after both coronary calcium scanning and exercise myocardial perfusion scintigraphy. J Am Coll Cardiol. 2007;49:1352–61. 68. Hounsfield GN. Computerized transverse axial scanning (tomography). 1. Description of system. Br J Radiol. 1973;46:1016–1022. 69. Achenbach S, Giesler T, Ropers D, et al. Detection of coronary artery stenoses by contrast-enhanced, retrospectively electrocardiographicallygated, multislice spiral computed tomography. Circulation. 2001; 103:2535–2538. 70. Nieman K, Cademartiri F, Lemos PA, Raaijmakers R, Pattynama PM, de Feyter PJ. Reliable noninvasive coronary angiography with fast submillimeter multislice spiral computed tomography. Circulation. 2002;106:2051–2054. 71. Vanhoenacker PK, Heijenbrok-Kal MH, Van Heste R, et al. Diagnostic performance of multidetector CT angiography for assessment of coronary artery disease: meta-analysis. Radiology. 2007;244:419–428. 72. Mowatt G, Cook JA, Hillis GS, et al. 64-Slice computed tomography angiography in the diagnosis and assessment of coronary artery disease: systematic review and meta-analysis. Heart. 2008;94:1386–1393. 73. Meijboom WB, Meijs MF, Schuijf JD, et al. Diagnostic accuracy of 64-slice computed tomography coronary angiography: a prospective, multicenter, multivendor study. J Am Coll Cardiol. 2008;52:2135–2144. 74. Budoff MJ, Dowe D, Jollis JG, et al. Diagnostic performance of 64-multidetector row coronary computed tomographic angiography for

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evaluation of coronary artery stenosis in individuals without known coronary artery disease: results from the prospective multicenter ACCURACY (Assessment by Coronary Computed Tomographic Angiography of Individuals Undergoing Invasive Coronary Angiography) trial. J Am Coll Cardiol. 2008;52:1724–1732. 75. Hausleiter J, Meyer T, Hadamitzky M, et al. Non-invasive coronary computed tomographic angiography for patients with suspected coronary artery disease: the Coronary Angiography by Computed Tomography with the Use of a Submillimeter resolution (CACTUS) trial. Eur Heart J. 2007;28:3034–3041. 76. Miller JM, Rochitte CE, Dewey M, et al. Diagnostic performance of coronary angiography by 64-row CT. N Engl J Med. 2008;359:2324–2336. 77. Di Carli MF, Hachamovitch R. New technology for noninvasive evaluation of coronary artery disease. Circulation. 2007;115:1464–1480. 78. Fearon WF, Tonino PA, De Bruyne B, Siebert U, Pijls NH. Rationale and design of the Fractional Flow Reserve versus Angiography for Multivessel Evaluation (FAME) study. Am Heart J. 2007;154:632–636. 79. Tonino PA, De Bruyne B, Pijls NH, et al. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med. 2009;360:213–224. 80. Pundziute G, Schuijf JD, Jukema JW, et al. Prognostic value of multislice computed tomography coronary angiography in patients with known or suspected coronary artery disease. J Am Coll Cardiol. 2007;49:62–70. 81. Min JK, Shaw LJ, Devereux RB, et al. Prognostic value of multidetector coronary computed tomographic angiography for prediction of all-cause mortality. J Am Coll Cardiol. 2007;50:1161–1170. 82. van Werkhoven JM, Schuijf JD, Gaemperli O, et al. Prognostic value of multislice computed tomography and gated single-photon emission computed tomography in patients with suspected coronary artery disease. J Am Coll Cardiol. 2009;53:623–632. 83. Berman DS, Hachamovitch R, Shaw L, Hayes SW, Germano G. Nuclear cardiology. In: Fuster V, Walsh RA, O’Rourke RA, PooleWilson PA, eds. Hurst’s the Heart.12th ed. McGraw-Hill, 2008. 84. Schuijf JD, Jukema JW, van der Wall EE, Bax JJ. The current status of multislice computed tomography in the diagnosis and prognosis of coronary artery disease. J Nucl Cardiol. 2007;14:604–612. 85. Cheng V, Gutstein A, Wolak A, et al. Moving beyond binary grading of coronary arterial stenoses on coronary computed tomographic angiography: insights for the imager and referring clinician. J Am Coll Cardiol Imaging. 2008;1:460–471. 86. Abidov A, Gallagher M, Chinnaiyan K, Mehta L, Wegner J, Raff G. Clinical effectiveness of coronary computed tomographic angiography in the triage of patients to cardiac catheterization and revascularization after inconclusive stress testing: results of a two-year prospective trial. J Nucl Cardiol. 2009; In press. 87. Berman DS. Fourth Annual Mario S. Verani, MD Memorial Lecture: noninvasive imaging in coronary artery disease: changing roles, changing players. J Nucl Cardiol. 2006;13:457–473. 88. Di Carli MF, Hachamovitch R. Hybrid PET/CT is greater than the sum of its parts. J Nucl Cardiol. 2008;15:118–122. 89. Di Carli MF, Dorbala S, Curillova Z, et al. Relationship between CT coronary angiography and stress perfusion imaging in patients with suspected ischemic heart disease assessed by integrated PET-CT imaging. J Nucl Cardiol. 2007;14:799–809. 90. Braunwald E. Epilogue: what do clinicians expect from imagers? J Am Coll Cardiol. 2006;47:C101–C103. 91. Dilsizian V, Bateman TM, Bergmann SR, Desprez R, Magram MY, Goodbody AE, et al. Metabolic imaging with beta-methyl-p-[(123)I]iodophenyl-pentadecanoicacid identifies ischemic memory after demand ischemia. Circulation 2005;112:2169–2174.

3

Acute ST Elevation Myocardial Infarction

ZELMIRA CURILLOVA S c OTT D. SOLOMON It is estimated that about 500 000 acute ST elevation myocardial infarctions (STEMI) occur per year in the United States [1]. Although a substantial number of patients die suddenly in the first few hours of an acute myocardial infarction (MI), subsequent morbidity and mortality remain high in those who survive. This review will discuss the utility and limitations of various imaging methods to assess cardiac structure and function following acute MI.

jâ•… PATHOPHYSIOLOGY Acute cessation of regional perfusion, most commonly following a thrombotic occlusion of an epicardial coronary artery, initiates a cascade of metabolic, functional, and structural changes in the myocardial tissue subtended by the occluded artery. An acute lack of oxygen leads to cessation of aerobic metabolism, accumulation of catabolites, tissue acidosis, cell membrane dysfunction with resulting intracellular edema, and subsequent myocyte death. The irreversible tissue injury begins approximately at 20 minutes of coronary occlusion. The wave of myocardial necrosis spreads from the subendocardium toward the subepicardium, reflecting higher oxygen consumption in the subendocardial layer. Tissue necrosis is also accompanied by interstitial edema and cellular infiltration with leukocytes and red blood cells, then later on with macrophages and fibroblasts, ultimately followed by the formation of dense collagenous scar [2]. Reversible ischemia, from transient coronary occlusion or demand-induced ischemia can lead to conditions of depressed myocardial function without necrosis such as short-term hibernation or acute myocardial stunning. It is clinically important to differentiate these conditions of viable dysfunctional myocardium from irreversible myocardial injury since myocardial contractile function will likely improve, provided there is no recurrent ischemia [2].

jâ•…C LI NICAL AND DIFFERENTIAL DIAGNOSIS OF STEMI The clinical diagnosis of STEMI requires symptoms compatible with acute coronary syndrome and presence of new (or presumably new, if no prior electrocardiogram [ECG] is available) ST elevations in at least 2 contiguous leads accompanied by a typical rise and fall of biochemical markers of myocardial necrosis [3]. The majority of STEMI result from an acute thrombotic coronary occlusion in the setting of atherosclerotic coronary disease. However, other coronary events such as coronary embolism, coronary dissection, vasospasm, arteritis, or trauma to coronary arteries can lead to similar clinical presentation. Larson et al observed that in a large cohort of patients referred for cardiac catheterization for suspected acute STEMI, no culprit coronary lesion was found in 14% and about 10% of patients had no angiographic evidence of coronary atherosclerosis [4]. Many factors limit the ability of ECG to reliably diagnose acute MI. There are medical conditions other than acute thrombotic coronary occlusion that can present with ST segment elevation on the ECG. Examples include acute pericarditis or myopericarditis, stress-induced cardiomyopathy (Takotsubo syndrome), Prinzmetal’s angina, hypothermia, intracranial hemorrhage, hyperkalemia, pulmonary embolism, Brugada syndrome, left ventricular (LV) hypertrophy, or an early repolarization ECG pattern [2,5]. On the other hand, there are clinical situations where MI or myocardial ischemia is suspected, but the patient has nondiagnostic ECG (e.g. left bundle branch block [LBBB], paced rhythm) or nonclassic ECG changes (eg, isolated posterior or right ventricular MI). The biochemical markers of myocardial injury can be missing in patients presenting early from the onset of symptoms. On the other hand, elevation of these biomarkers is not necessarily indicative of ischemic etiology of myocardial damage and can also be observed in conditions such as acute myocarditis, stress-induced cardiomyopathy, acute pulmonary embolism, or sepsis.

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jâ•… ROLE OF IMAGING The time from onset of symptoms to the diagnosis and treatment of acute STEMI is crucial to maximize myocardial salvage. In cases where the clinical diagnosis of STEMI is clear, the focus should be on early reperfusion therapy. Therefore, performing additional imaging studies would not add any incremental diagnostic value and would further delay treatment. However, there is a role for additional imaging in clinical situations where the initial diagnosis of acute STEMI is unclear or where medical condition with contraindication to fibrinolytic or anticoagulation therapy is suspected (e.g. aortic dissection, pericarditis). There is an established role of cardiac imaging following acute presentation with STEMI that includes detection of mechanical complications of MI, post-MI risk stratification, assessment of infarct size, and overall prognosis (Table 3.1).

jâ•… ECH OCARDIOGRAPHY Major advantage of echocardiography over other imaging modalities in acute clinical situations is its wide availability and portability. As is the case with other imaging modalities, the role of echocardiography in patients presenting with acute STEMI is limited to situations where diagnosis of STEMI is uncertain or if other noncoronary etiology of acute chest pain or ST elevations is suspected.

Echocardiography is usually the first-line imaging modality for the detection of post-MI complications. Also explored in this section is the role of echocardiography in the assessment of infarct size, post-MI risk stratification, and prognosis. Diagnosis and Management

Initial Diagnosis and Differential Diagnosis A resting transthoracic echocardiogram is indicated for evaluation of patients with acute chest pain and suspected myocardial ischemia with nondiagnostic ECG or laboratory markers [6]. Common diagnostic dilemma includes patients presenting with chest pain and new or presumably new LBBB or ventricular-paced rhythm on the ECG. According to American College of Cardiology/American Heart Association practice guidelines for management of patients with acute STEMI, fibrinolytic therapy should be administered to STEMI patients with symptom onset within the previous 12 hours and new or presumably new LBBB, in the absence of contraindications [1]. Although patients with new LBBB presenting with MI belong to the high-risk group and achieve greater benefit from fibrinolytic therapy, there are often concerns about the validity of ECG criteria for MI diagnosis in this setting and about potential risks of therapy. Larson et al evaluated the frequency of false-positive catheterization laboratory activation in patients with suspected STEMI referred to a tertiary

jâ•… Table 3.1â•… Recommendations from the American College of Cardiology/American Heart Association guidelines for the management of patients with STEMI Class I Recommendation

Class IIa Recommendation

Class III Recommendation

1.â•‡Patients with STEMI should have a portable chest X-ray, but this should not delay implementation of reperfusion therapy (unless a potential contraindication, such as aortic dissection, is suspected).

ortable echocardiography is reasonable P to clarify the diagnosis of STEMI and allow risk stratification of patients presenting with chest pain, especially if the diagnosis of STEMI is confounded by left bundle branch or pacing or there is suspicion of posterior STEMI with anterior ST depressions.

S ingle photon emission computed tomography radionuclide imaging should not be performed to diagnose STEMI in patients for whom the diagnosis of STEMI is evident on the electrocardiogram.

2.â•‡Imaging studies such as a highquality portable chest X-ray, transthoracic and/or transesophageal echocardiography, and a contrastenhanced chest computed tomography or magnetic resonance imaging scan should be used to differentiate STEMI from aortic dissection in patients for whom the distinction is initially unclear. STEMI, ST elevation myocardial infarctions. From Ref. 1.

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cardiovascular center. In a subgroup of patients who presented with new or presumed new LBBB, no culprit coronary lesion was found in 44% and no angiographic evidence of coronary disease was found in 27% of these patients [4]. In this clinical scenario, additional valuable information can be derived from a bedside echocardiogram. The location and extent of new wall motion abnormalities detected helps triage these patients to the most appropriate management strategy. Myocardial injury in the left circumflex coronary artery territory can be ECG silent on a standard 12-lead ECG or the true posterior MI may manifest only by tall R waves and ST segment depression in the right precordial leads [7]. Confirmatory data from a bedside echocardiogram detecting new wall motion abnormalities in the left circumflex territory are very helpful in clinical decision making. ST elevations on the ECG in patients with chest pain can also be due to an acute pericarditis or myopericarditis. Given the elevated risk of pericardial hemorrhage and tamponade after fibrinolytic therapy in patients with pericarditis, it is important to differentiate it from acute STEMI [8]. Presence of pericardial effusion has been described in approximately 60% of acute pericarditis cases [9]. Therefore, if a pericardial effusion is detected on the echocardiogram, it favors diagnosis of pericarditis. However, an absence of pericardial effusion does not exclude acute pericarditis. Conversely, the detection of a new wall motion abnormality on the echocardiogram favors diagnosis of acute MI. Nevertheless, wall motion abnormalities and elevation of biomarkers of myocardial necrosis can also be present in myopericarditis. More diffuse pattern and noncoronary distribution of wall motion abnormalities in acute myopericarditis can help to differentiate it from an acute MI. In clinical practice, the differentiation of acute STEMI and acute pericarditis/myopericarditis can be challenging and in some cases it may be necessary to perform coronary angiogram to rule out an acute MI [10].

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The transthoracic echocardiogram can detect the presence of a dissection flap in the ascending thoracic aorta or a new aortic insufficiency in the setting of an acute type A aortic dissection. Nienaber et al reported low sensitivity of about 59% but higher specificity of 83% for the detection of thoracic aortic dissection by transthoracic echocardiography [11]. Echocardiography can visualize thrombi in the right-sided cardiac chambers, main pulmonary artery, or proximal main pulmonary artery branches and lead to diagnosis of pulmonary embolism. Echocardiographic findings of right ventricular dilatation and hypokinesis are helpful in the evaluation of patients with known or suspected acute pulmonary embolism to guide thrombolytic therapy or thrombectomy. However, echocardiogram is not recommended for a routine initial evaluation of patients to establish the diagnosis of acute pulmonary embolism [6,12]. The regional wall motion abnormality on the echocardiogram is less often detected with small infarcts due to tethering of the infarcted area to the surrounding, normally contracting myocardium. When wall motion abnormality is detected, it can be difficult to differentiate between acute and chronic MI, unless a baseline pre-event echocardiogram is available for comparison. Chronic MI tends to be associated with wall thinning, whereas acute MI can display increased wall thickness due to myocardial edema and inflammation.

Post-MI Complications In patients with acute decompensation post-MI or unstable hemodynamics, echocardiography is a valuable tool to assess for post-MI mechanical complications such as ventricular septal defect, free wall rupture/tamponade, ventricular pseudoaneurysm, acute mitral regurgitation, right ventricular involvement or ventricular aneurysm, and thrombus [6] (Figures 3.1 and 3.2). Acute mitral regurgitation post-MI can be due to papillary muscle dysfunction or rupture or

3 . 1 â•… Post–myocardial infarction mechanical complication following a left anterior descending coronary artery infarct. There is a ventricular septal defect with left to right flow located in the distal interventricular septum (arrow).

FIGURE

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F I G U R E 3 . 2 â•… Giant left ventricular aneurysm (arrowheads) in a patient

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with nonreperfused anterior myocardial infarction. LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle.

due to acute systolic anterior motion of the mitral valve. Because the posteromedial papillary muscle is supplied by a single coronary artery, rupture of the posteromedial Â�papillary muscle is more common than rupture of the anterolateral papillary muscle that has a dual blood supply (Figure 3.3). Another possible mechanical post-MI complication is an acute dynamic LV outflow tract obstruction with systolic anterior motion of the mitral valve and mitral regurgitation. This complication is seen more commonly after an acute anterior MI in elderly females with preexisting upper septal hypertrophy. The compensatory hyperdynamic motion of the inferolateral wall leads to altered geometry of the mitral valve apparatus and systolic anterior motion resulting in dynamic LVOT obstruction and mitral regurgitation [2].

Transesophageal Echocardiography Transesophageal echocardiogram (TEE) is an important imaging tool in difficult clinical situations where transthoracic images are nondiagnostic, for example, in intubated postoperative patients in the critical care unit. In patients with acute decompensation, post-MI TEE is considered superior to transthoracic echo to diagnose acute severe mitral regurgitation due to papillary muscle rupture where the timely diagnosis and urgent surgical treatment are crucial for survival. TEE is also commonly employed in assessment of patients with suspected acute aortic dissection (Figure 3.4). The advantage of the TEE over chest computed tomography (CT) or magnetic resonance imaging in the evaluation for aortic dissection is its portability and no need for contrast administration. TEE is usually the preferred modality in hemodynamically unstable patients or in patients with significant renal impairment when both the iodinated contrast and gadolinium administration are undesirable.

B F I G U R E 3 . 3 â•… Post–myocardial infarction mechanical complications.

Ruptured posteromedial papillary muscle head (arrow) prolapsing into the left atrium (A) with associated severe eccentric mitral regurgitation (B).

Risk Stratification and Prognosis Revascularization of the culprit epicardial coronary artery is necessary for myocardial salvage in acute STEMI. However, a successful revascularization of the epicardial coronary artery does not always translate into successful reperfusion of the myocardium at the microvascular level. Using the wall motion abnormalities to assess the extent of myocardial damage, acutely post-MI is confounded by the presence of dysfunctional but viable myocardium due to myocardial stunning. In the reperfused stunned myocardium, improvement in regional contractility starts 1 to 2 days postreperfusion and continues over several weeks to months [2].

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epicardial coronary artery have shown that approximately one-third of patients lack myocardial reperfusion as evidenced by the presence of myocardial no-reflow zones. Absence of the no-reflow zone shortly after revascularization was predictive of an improvement in global and regional myocardial function and lack of adverse ventricular remodeling [15–17]. Lepper et al used intravenous myocardial contrast just prior to primary coronary angioplasty in patients with acute STEMI to define the myocardial area at risk and then at 24 hours after angioplasty to define the no-reflow regions. Authors concluded that the area ratio (no-reflow area divided by area at risk) of 50% was associated with improvement in regional wall motion abnormalities and regional coronary flow reserve [18]. Galiuto et al used myocardial contrast echo to assess the extent of microvascular damage in patients 1 day after successfully reperfused STEMI. At multivariable analysis, the thrombolysis in myocardial infarction flow grade ,3 after percutaneous intervention and the endocardial length of contrast defect .25% were independent predictors of adverse left ventricular remodeling at 6-month follow-up [19] (Figure 3.5).

Low-Dose Dobutamine Echocardiography

B F I G U R E 3 . 4 â•…Transesophageal echocardiogram showing type A aor-

tic dissection with a dissection flap (arrow) in the ascending thoracic aorta (A) and color flow in the true lumen (B).

Myocardial Contrast Echocardiography This technique uses an injection of sonicated microbubbles to image myocardial perfusion. One can look at the replenishment of myocardial opacification after a destruction pulse that eliminates microbubbles in the imaging field. Myocardial contrast signal intensity is considered to reflect microvascular integrity and it has been shown to Â�correlate directly with capillary density and indirectly with collagen content in the biopsied myocardium [13]. Contrast Â�perfusion assessed at 10 to 15 seconds during destructionreplenishment imaging has been shown to correlate well with infarct size in an animal model of acute MI [14]. Studies performed using an intracoronary myocardial contrast injection after successful recanalization of the culprit

Another method for the detection of dysfunctional but Â�viable myocardium early post-MI is the demonstration of contractile improvement with low-dose dobutamine. Hillis et al Â�compared the myocardial contrast echo and low-dose Â�dobutamine Â�echocardiography (DE) early post-MI for Â�predicting LV Â�functional recovery. In their study, normal contrast opacification predicted myocardial functional recovery with a positive predictive value of 63% and a negative Â�predictive value of 73%. Residual contractility during low-dose DE had a Â�positive predictive value of 82% and a negative predictive value of 72%. The authors concluded that the low-dose DE was superior to myocardial contrast echo in predicting functional recovery of dysfunctional myocardium early after acute MI [20].

Post-MI Prognosis Following an acute MI, there are many established prognostic indicators such as the degree of systolic dysfunction, LV dilatation, mitral regurgitation, extent of coronary artery Â�disease, and presence of heart failure [2]. In addition, prognostic value of myocardial viability detected early post-MI was evaluated. In a study by Swinburn and Senior using dobutamine stress echo in stable post-MI patients, the independent predictors of death and nonfatal MI were age and systolic wall thickening index at low-dose dobutamine. The low-dose dobutamine response also provided incremental value over clinical information and LV systolic function at rest [21]. Dwivedi et al demonstrated that the extent of myocardial viability by myocardial contrast echo was a powerful independent predictor of cardiac death or nonfatal MI in a cohort of stable patients early post-MI [22]. In addition, other echocardiographic parameters such as a noninvasive

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F I G U R E 3 . 6 â•…Myocardial late gadolinium enhancement in the basal short-axis view in a patient with transmural myocardial infarction in the posterior descending artery territory (white arrowheads) with evidence of left ventricular thrombus (black arrow).

Delayed-enhancement CMR is a more sensitive technique than echocardiography for the detection of LV thrombus [25,26] (Figure 3.6). CMR findings early after acute MI can provide information about infarct size, viable myocardium, and an overall prognosis. Diagnosis and Management B F I G U R E 3 . 5 â•…A, Myocardial contrast echocardiography in 4-chamber

view shows a large endocardial contrast defect in the lateral wall (between arrows) with normal end diastolic volume. B, Two-dimensional echocardiogram at 6-month follow-up shows enlarged left ventricle. Adapted from Ref. 19.

estimation of LV filling pressure using E/E' ratio or persistent restrictive mitral inflow pattern were shown to be predictive of survival after acute MI [23,24].

jâ•… CARDIAC MAGNETIC RESONANCE In patients with clinical suspicion of acute STEMI and diagnostic ECG or elevated biomarkers of acute myocardial injury, there is usually little incremental value of additional diagnostic workup since this would only further delay timely revascularization. Nevertheless, if clinical presentation does not add up, cardiac magnetic resonance (CMR) tissue characterization can offer important additional clues to guide the appropriate patient management. CMR images can also be used to diagnose conditions that can mimic acute MI such as aortic dissection, myocarditis, pericarditis, or acute pulmonary embolism.

Late Gadolinium Enhancement Gadolinium chelates such as gadolinium–diethylenetriamine-pentaacetic acid (Gd-DTPA) are thought to passively diffuse throughout the extracellular space. The proposed mechanism of late gadolinium enhancement (LGE) acutely after MI involves an increase in extracellular volume of distribution in the myocardial tissue after myocyte death (loss of cell membrane integrity) and altered washin and washout kinetics in the infarct zone. In the setting of chronic MI, myocytes have been replaced by collagenous scar with increased interstitial space and therefore increased extracellular volume of distribution when compared to tightly packed myocytes of the normal myocardium [27]. Kim et al [28] studied the relationship of LGE to myocardial injury and infarct age in dogs with experimental MI and after transient myocardial ischemia. The authors used T1-weighted inversion recovery fast gradient echo pulse sequences, acquired 20 to 30 minutes after an intravenous injection of Gd-DTPA, to image canine hearts in vivo and ex vivo. The images were also compared with histopathology using triphenyltetrazolium chloride (TTC) staining for necrosis. They demonstrated that the spatial extent of LGE on CMR images closely correlated with the spatial extent of myocardial necrosis by TTC staining

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at 1 and 3 days post-MI and with the extent of collagenous scar at 8 weeks. The wall thickening at 3 days was impaired in both, regions with infarcted myocardium and transiently ischemic myocardium; however LGE was present only in regions with infarcted myocardium. At 8 weeks postevent, the wall thickening in regions of transient ischemia normalized. The authors concluded that both acute and chronic myocardial infarcts showed LGE; however, myocardial injury without necrosis did not hyperenhance despite the presence of myocardial stunning. The absolute volume of hyperenhanced regions at day 3 postevent had decreased approximately by a factor of 3.4 by 8 weeks postevent, suggesting that spatial extent of collagenous scar at 8 weeks was smaller than spatial extent of acute myocardial necrosis likely due to infarct shrinkage. Similar findings were previously described by Reimer and Jennings, who found about a 4-fold decrease in infarct volume between day 4 and day 28 postevent on histology [29].

T2-weighted Techniques Acute MI is accompanied by myocardial edema [30]. In edematous tissues, hydrogen protons are more frequently bound in free water and display longer transverse relaxation time (T2 time). Higgins et al first demonstrated good linear correlation between T2 relaxation time and myocardial water content in a dog model of acute MI [31]. More than 20 years ago McNamara et al imaged patients early after an acute MI using spin echo pulse sequence and observed that infarcted regions had significantly prolonged T2 relaxation time (∼81 milliseconds) compared to normal myocardium (∼42 milliseconds) [32]. T2-weighted pulse sequences display edematous myocardium as having higher signal intensity than the remote myocardium. The T2-weighted technique has been used to image myocardial edema in conditions such as acute MI, acute myocarditis, or acute rejection after heart transplant [33,34]. Abdel-Aty et al studied 15 dogs with transient coronary occlusion and after reperfusion using T2-weighted inversion recovery fast spin echo sequences with blood and fat suppression. They observed that function in the affected segments deteriorated very early after the coronary artery occlusion. This was followed by the onset of myocardial edema that was visually apparent as high T2 signal intensity areas in ∼28 minutes after coronary occlusion. Myocardial edema was detected in the dysfunctional segments even in dogs without evidence of concurrent myocardial necrosis on LGE images [35]. It has been known that both acute and chronic infarctions exhibit LGE regardless of infarct age [28]. T2-weighted techniques were used to differentiate acute from chronic MI. In another study by Abdel-Aty et al, the addition of T2-weighted images to LGE examination yielded a specificity of 96% to differentiate acute from chronic MI [36]. The ability to localize and differentiate acute from chronic MI can be helpful in clinical situations

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where the biomarkers or ECG are equivocal or when a patient has a history of prior infarct and presents with a possible new event. Infarct-associated edema is thought to persist for 2 to 3 weeks after an acute event, so it can also be used as a tissue memory marker of recent MI [37]. Acute stress-induced cardiomyopathy (Takatsubo cardiomyopathy) can clinically present very similar to acute STEMI or acute coronary syndrome. It is characterized by a typical pattern of wall motion abnormalities with apical ballooning. However, there is no angiographic evidence of obstructive coronary stenosis and no evidence of irreversible myocardial injury by LGE technique [38]. Abdel-Â�Aty et al performed CMR in 7 patients with stress-induced Â�cardiomyopathy and found T2-hyperintense areas matching with areas of myocardial dysfunction, suggesting the presence of myocardial edema in dysfunctional segments. Both abnormalities resolved at follow-up. No significant LGE was observed in the dysfunctional segments. Combination of T2-weighted images and LGE can also be helpful in differentiating acute MI from acute myocarditis. The pattern of myocardial involvement in myocarditis often proceeds from focal to global pattern. The LGE is mostly subepicardial or midwall and often multifocal [33,39,40].

Risk Stratification and Prognosis

Areas at Risk and Infarct Size It has been suggested that T2-hyperintense regions with myocardial edema after acute MI represent areas at risk and correlate well with the extent of acute hypokinesis. The spatial extent of regions with increased T2 signal intensity is larger than the extent of irreversible injury by LGE [41,42] (Figure 3.7). It has been observed that the increase in myocardial T2 signal intensity after acute coronary occlusion develops approximately 1 day postevent and resolves in few months [43,44]. The difference between the area at risk and LGE area is the amount of salvageable myocardium [45]. In other words, the T2-hyperintense regions without LGE represent dysfunctional but viable myocardium [41,42,45,46]. When compared to single photon emission computed tomography for quantification of area at risk and infarct size, advantages of CMR include no radiation exposure, Â�better spatial resolution, and easier logistics. CMR is becoming an attractive imaging technique for evaluating the effectiveness of different adjunctive therapies in acute MI. Good Â�reproducibility [47] and higher image resolution [48] and therefore better ability to detect small infarcts would Â�translate into smaller number of patients needed for clinical trials. Another potential clinical application is in patients presenting late after the onset of MI symptom. Assessment of area at risk compared to area of irreversible injury can help to differentiate between patients who have completed their infarct and patients with potentially salvageable myocardium at risk who would benefit from revascularization [49].

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F I G U R E 3 . 7 â•… Cardiac magnetic resonance in acute nontransmural myocardial infarction. T2-weighted and postcontrast T1-weighted late gadolinium enhancement images showing infarction related transmural edema but only subendocardial necrosis. Modified from Ref. 33.

Improvement of Function, LV Remodeling, and Prognosis Post-MI The main goal of successful reperfusion therapy in acute MI is myocardial salvage with reestablishment of contractile function and improvement in prognosis. Ventricular wall motion at rest cannot be used early post-MI to predict myocardial viability because both necrotic and stunned myocardium have impaired contractile function. Choi et al investigated the utility of LGE in patients within 7 days from an acute MI to predict recovery of regional and global myocardial function. The authors found that the improvement in segmental contractile function on the follow-up scan 8 to 12 weeks post-MI was inversely related to the transmural extent of LGE on the initial scan. For example, 77% of segments with no late enhancement or 67% of segments with 1% to 25% transmural extent LGE showed improved function, but only 5% of segment with .75% transmural extent enhancement improved on follow-up. The best predictor for improvement in global LV systolic function was the amount of dysfunctional but noninfarcted myocardium on the initial scan [50]. Changes in ventricular architecture post-MI with LV dilatation (LV remodeling) depend on infarct size as well as rate of infarct healing and wall stress [51]. A study by Ito et al [16] used an intracoronary injection of echo contrast to image microvascular obstruction or no-reflow zone following successful percutaneous coronary intervention for acute anterior MI. The results indicated that the presence of microvascular obstruction adversely affects LV remodeling perhaps by attenuating the beneficial effect of early reperfusion. At the center of the infarct, there is an area of microvascular obstruction also called no-reflow zone where capillaries become injured and occluded by dying blood cells and debris. Despite restoration of blood flow in the epicardial coronary artery, these areas of no-reflow do not reperfuse. Several studies have validated the microvascular obstruction imaging by CMR against pathology and angiographic myocardial blush score [52,53].

Wu et al looked at patients who underwent CMR examination early after acute MI and then were followed up clinically for a mean of 16 6 5 months. Microvascular obstruction was defined as subendocardial hypoenhancement surrounded by hyperenhanced areas of infarcted myocardium seen 1 to 2 minutes after the gadolinium contrast injection on myocardial perfusion images. The risk of adverse events (cardiac death, reinfarction, heart failure, stroke, or rehospitalization for unstable angina) increased with increasing extent of LGE. Nonetheless, even after infarct size was controlled for, the presence of microvascular obstruction remained predictive of postinfarction complications [54]. Similarly, in the study by Hombach et al in patients imaged early after acute MI, presence of microvascular obstruction on late enhancement images was a significant predictor of major adverse cardiac events (death, MI, rehospitalization for cardiac failure, unstable angina, or revascularization) as was LV end-diastolic volume and LV ejection fraction. The infarct size, microvascular obstruction, and amount of transmural scar were predictive of adverse LV remodeling [55] (Figure 3.8).

jâ•… CARDIAC CT The role of CT in the setting of acute MI is limited to situations with atypical clinical presentation and nondiagnostic ECG findings when noncoronary etiologies of chest pain are suspected (eg, aortic dissection, acute pulmonary embolism). Cardiac CT can be used for the detection of post-MI complications and for the assessment of infarct size and early post-MI viability. Diagnosis and Management Clinical features of acute MI can overlap with other acute conditions such as pulmonary embolism, aortic dissection, or dissecting aortic hematoma. Contrast-enhanced CT is a fast and reliable tool for detection of aortic dissection

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F I G U R E 3 . 8 â•… Basal short-axis slice late gadolinium enhancement in a

patient with inferolateral myocardial infarction with manual quantification of enhanced myocardium and persistent microvascular obstruction (dark central zone within the myocardium with high signal intensity). Adapted from Ref. 55.

with pooled sensitivity of 100% and specificity of 98% in recent meta-analysis by Shiga et al [56]. CT pulmonary angiogram is evolving into a primary imaging modality for the detection of acute pulmonary embolism, especially in the era of multidetector-raw CT with submillimeter spatial resolution [57]. Contrast-enhanced CT scans are commonly performed for the evaluation of symptoms suggestive of acute pulmonary embolism or aortic dissection but can incidentally detect areas of myocardial hypoenhancement that could trigger consideration of an acute MI [58,59]. CT can also detect complications of acute MI such as LV thrombus or pericardial effusion. Based on the CT attenuation coefficient (Hounsfield units), one can differentiate simple fluid from hemorrhagic pericardial effusion. Risk Stratification and Prognosis Similar to CMR, multidetector CT (MDCT) can detect areas of irreversible myocardial injury on delayed postcontrast images using iodinated contrast. Areas of delayed enhancement are thought to reflect an increased interstitial space due to myocyte damage in the acute phase or an increased extracellular volume of distribution due to collagenous scar in the chronic phase of the infarct. Both animal and human studies comparing the 2 techniques reported good agreement for the detection of hyperenhanced regions [60,61]. Lardo et al compared the delayed enhancement on MDCT to histopathology in an animal model and concluded that the spatial extent of acute and

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chronic MI can be accurately determined and quantified with contrast-enhanced MDCT [62]. Contrast-enhanced cardiac CT is also able to detect areas of hypoenhancement on the early postcontrast images that correlate with areas of hypoenhancement on first-pass perfusion CMR [60,63]. Areas of hypoenhancement on early postcontrast images are thought to represent underperfused myocardial regions due to obstructed infarct-related artery and microvascular obstruction in the setting of acute MI or decreased capillary density of the myocardial scar in the setting of chronic MI [62]. Habis et al evaluated the usefulness of 64-slice CT delayed enhancement without iodinated contrast reinjection immediately after coronary angiography in a cohort of acute MI patients where 94% of patients had STEMI. Mean delay between the coronary angiography and CT was 24 6 11 minutes and the viability by CT was defined as no or ,50% subendocardial delayed enhancement. Authors Â�compared the CT viability results with low-dose DE performed 2 to 4 weeks post-MI. On segmental analysis, agreement was noted in 97% of segments; the sensitivity, specificity, positive, and negative predictive values were 98%, 94%, 99%, and 79%, respectively, for detecting Â�viable segments very early post-MI [64] (Figure 3.9). Similarly, Sato et al performed no reinjection CT delayed enhancement immediately following coronary stenting in patients with acute STEMI. Patients with 75% transmural extent of delayed enhancement had significantly higher incidence of adverse LV remodeling at 6-month Â�follow-up and were more often rehospitalized for heart failure Â�compared to patients with ,75% enhancement [65]. Both these studies suggest that CT delayed-Â�enhancement Â�patterns early after STEMI may provide important information about myocardial viability. Limitations of MDCT include the need for iodinated contrast and radiation exposure, especially of concern when both early and delayed postcontrast images are acquired. Development of new imaging protocols and better technology aims to minimize the radiation dose. Examples include lower dose CT angiography with prospective ECG gating in step and shoot mode, retrospective ECG gating with tube current modulation or acquisition of the whole heart volume in a single rotation in one R-R interval with 320-slice CT [66–69].

jâ•… NUC LEAR TECH NIQUES Radionuclide imaging has limited clinical application for diagnosis of acute MI and should be restricted to limited situations where the initial diagnosis of acute MI is not clear. Application of nuclear imaging techniques for assessment of area at risk, infarct size, myocardial salvage, and inducible ischemia after acute MI will be discussed.

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F I G U R E 3 . 9 â•… (A) 64-slice computed tomography (CT) scan 51 Â�minutes

after a primary angioplasty for acute myocardial infarction showing hyperenhancement of the inferolateral wall (arrows). LowÂ� subendocardial dose dobutamine echocardiography confirmed myocardial viability of these segments. (B) 64-slice CT scan 21 minutes after left anterior descending artery reperfusion showing transmural hyperenhancement (arrows) in mid short axis (a) and 4-chamber (b) views. This patient was confirmed to have no viability by low-dose dobutamine echo in all involved segments. Ao, aorta; LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle. Modified from Ref. 64.

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Diagnosis and Management

Infarct Avid Imaging First attempts to directly visualize areas of MI were based on hot spot imaging agents such as 99mTc-pyrophosphate and 111In-antimyosin. 99m Tc-pyrophosphate is mostly used for bone scanning. The exact mechanism for its affinity to myocardial necrosis is not entirely understood, but it has been proposed that 99mTc-pyrophosphate targets calcium phosphate in the mitochondria of severely injured myocytes. Maximum uptake occurs in 24 to 72 hours after acute infarction and lasts for 6 to 10 days. The shortcomings include 2 to 3 days of accumulation delay in nonreperfused MI, low sensitivity for subendocardial infarcts, and superimposed bone activity that limits reliable image interpretation. Falsepositive results can be seen due to the presence of cardiac

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calcifications (eg, valvular calcifications, calcified LV aneurysm), cardiac amyloidosis, myocarditis, cardiac metastasis, or secondary hyperparathyroidism. There is reduced sensitivity for detecting small or nontransmural infarcts. Infarct avid scintigraphy can be also performed using 111 In-antimyosin antibody fragments that bind to the exposed intracellular myosin heavy chain after loss of cell membrane integrity. The image acquisition is recommended at about 48 hours after injection to minimize the blood pool activity. 111In-antimyosin antibody imaging of MI has better specificity when compared to 99mTc-pyrophosphate imaging. None of the infarct avid tracer described is currently being used in practice for diagnosis of MI. There is a significant delay in tracer accumulation in the infarct zone or delay required for imaging, making their use not practical [70,71].

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Myocardial Perfusion Imaging

jâ•… REF ERENCES

After an intravenous injection of 99mTc-sestamibi or 99m Tc-tetrofosmin, the radiotracer enters myocytes proportionally to myocardial blood flow. Once it becomes intracellular, it has a very slow washout rate, independent of myocardial blood flow. Because of its pharmacokinetic properties, 99mTc-sestamibi or 99mTc-tetrofosmin can be injected during acute presentation to the hospital and imaged few hours later after stabilization or revascularization, and the images will reflect tracer uptake at the time of injection [72]. Myocardial perfusion imaging at rest using these 99m Tc-labeled radiotracers can be used for the diagnosis of acute MI in patients with chest pain in whom the conventional measures are nondiagnostic. Findings of prior studies show high sensitivity and high negative predictive value of resting perfusion for acute MI [73–75]. The perfusion defects at rest, however, do not distinguish between acute ischemia, acute MI, or prior MI. Myocardial stress and rest perfusion imaging with 99m Tc-sestamibi, 99mTc-tetrofosmin, or 201Thallium chloride tracers can be used to assess the presence and extent of residual inducible ischemia after STEMI following successful fibrinolytic therapy for further risk stratification and to determine the need for cardiac catheterization prior to discharge. Other accepted indications for nuclear imaging after STEMI include evaluation of functional significance of coronary lesion previously identified on angiography, assessment of left ventricular function, or assessment of right ventricular function in suspected right ventricular infarction using a first-pass or equilibrium radionuclide angiography [76].

â•‡ 1. Antman EM, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction—executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction). Circulation. 2004;110(5):588–636. â•‡ 2. Libby P, Braunwald E. Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine. 8th ed. Philadelphia: Saunders/Elsevier;2008. â•‡ 3. Cannon CP, et al. American College of Cardiology key data elements and definitions for measuring the clinical management and outcomes of patients with acute coronary syndromes. A report of the American College of Cardiology Task Force on Clinical Data Standards (Acute Coronary Syndromes Writing Committee). J Am Coll Cardiol. 2001;38(7):2114–2130. â•‡ 4. Larson DM, et al. “False-positive” cardiac catheterization laboratory activation among patients with suspected ST-segment elevation myocardial infarction. JAMA. 2007;298(23):2754–2760. â•‡ 5. Wang K, Asinger RW, Marriott HJ. ST-segment elevation in conditions other than acute myocardial infarction. N Engl J Med. 2003;349(22):2128–2135. â•‡ 6. Douglas PS, et al. ACCF/ASE/ACEP/ASNC/SCAI/SCCT/SCMR 2007 appropriateness criteria for transthoracic and transesophageal echocardiography: a report of the American College of Cardiology Foundation Quality Strategic Directions Committee Appropriateness Criteria Working Group, American Society of Echocardiography, American College of Emergency Physicians, American Society of Nuclear Cardiology, Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Computed Tomography, and the Society for Cardiovascular Magnetic Resonance. Endorsed by the American College of Chest Physicians and the Society of Critical Care Medicine. J Am Soc Echocardiogr. 2007;20(7):787–805. â•‡ 7. Matetzky S, et al. Significance of ST segment elevations in posterior chest leads (V7 to V9) in patients with acute inferior myocardial infarction: application for thrombolytic therapy. J Am Coll Cardiol. 1998;31(3):506–511. â•‡ 8. Spodick DH. Acute pericarditis: current concepts and practice.â•‡ JAMA. 2003;289(9):1150–1153. â•‡ 9. Imazio M, et al. Day-hospital treatment of acute pericarditis: a management program for outpatient therapy. J Am Coll Cardiol. 2004;43(6):1042–1046. 10. Salisbury A, et al. Frequency and predictors of urgent coronary angiography in patients with acute pericarditis. Mayo Clin Proc. 2009;84(1):11–15. 11. Nienaber CA, et al. The diagnosis of thoracic aortic dissection by noninvasive imaging procedures. N Engl J Med. 1993;328(1):1–9. 12. Cheitlin MD, et al. ACC/AHA/ASE 2003 guideline update for the clinical application of echocardiography—summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/ASE Committee to Update the 1997 Guidelines for the Clinical Application of Echocardiography). Circulation. 2003;108(9):1146–1162. 13. Shimoni S, et al. Microvascular structural correlates of myocardial contrast echocardiography in patients with coronary artery disease and left ventricular dysfunction: implications for the assessment of myocardial hibernation. Circulation. 2002;106(8):950–956. 14. Coggins MP, et al. Noninvasive prediction of ultimate infarct size at the time of acute coronary occlusion based on the extent and magnitude of collateral-derived myocardial blood flow. Circulation. 2001;104(20):2471–2477. 15. Ito H, et al. Lack of myocardial perfusion immediately after successful thrombolysis. A predictor of poor recovery of left ventricular function in anterior myocardial infarction. Circulation. 1992;85(5):1699–1705. 16. Ito H, et al. Clinical implications of the “no-reflow” phenomenon. A predictor of complications and left ventricular remodeling in reperfused anterior wall myocardial infarction. Circulation. 1996;93(2):223–228.

Risk Stratification and Prognosis Myocardial perfusion defect at the time of initial presentation reflects the myocardium at risk. Subsequent perfusion defect after reperfusion therapy predischarge reflects final infarct size. The difference between these 2 measurements is the amount of myocardium salvaged. Multiple studies demonstrated the value of 99mTc-sestamibi in the quantification of infarct size and myocardial salvage with reperfusion therapy in the setting of acute MI [77]. The end points of infarct size and myocardial salvage have also been used to compare effectiveness of different treatment strategies in MI [78]. Infarct size measured by 99mTc sestamibi imaging shows a close correlation with directly measured infarct size in pathology specimens, left ventricular ejection fraction, regional wall motion, and myocardial enzyme release [79–83]. The infarct size, myocardial salvage index, extent and severity of stress-induced defects, and reversibility score on myocardial perfusion imaging in patients after acute MI were shown to predict short-term and long-term patient outcome [84–87].

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17. Kenner MD, et al. Ability of the no-reflow phenomenon during an acute myocardial infarction to predict left ventricular dysfunction at one-month follow-up. Am J Cardiol. 1995;76(12):861–868. 18. Lepper W, et al. Assessment of myocardial reperfusion by intravenous myocardial contrast echocardiography and coronary flow reserve after primary percutaneous transluminal coronary angioplasty [correction of angiography] in patients with acute myocardial infarction. Circulation. 2000;101(20):2368–2374. 19. Galiuto L, et al. The extent of microvascular damage during myocardial contrast echocardiography is superior to other known indexes of postinfarct reperfusion in predicting left ventricular remodeling: results of the multicenter AMICI study. J Am Coll Cardiol. 2008;51(5):552–559. 20. Hillis GS, et al. Comparison of intravenous myocardial contrast echocardiography and low-dose dobutamine echocardiography for predicting left ventricular functional recovery following acute Â�myocardial infarction. Am J Cardiol. 2003;92(5):504–508. 21. Swinburn JM, Senior R. Myocardial viability assessed by dobutamine stress echocardiography predicts reduced mortality early after acute myocardial infarction: determining the risk of events after myocardial infarction (DREAM) study. Heart. 2006;92(1):44–48. 22. Dwivedi G, et al. Prognostic value of myocardial viability detected by myocardial contrast echocardiography early after acute myocardial infarction. J Am Coll Cardiol. 2007;50(4):327–334. 23. Hillis GS, et al. Noninvasive estimation of left ventricular filling pressure by E/e’ is a powerful predictor of survival after acute myocardial infarction. J Am Coll Cardiol. 2004;43(3):360–367. 24. Temporelli PL, et al. Doppler-derived mitral deceleration time as a strong prognostic marker of left ventricular remodeling and survival after acute myocardial infarction: results of the GISSI-3 echo substudy. J Am Coll Cardiol. 2004;43(9):1646–1653. 25. Mollet NR, et al. Visualization of ventricular thrombi with contrastenhanced magnetic resonance imaging in patients with ischemic heart disease. Circulation. 2002;106(23):2873–2876. 26. Srichai MB, et al. Clinical, imaging, and pathological characteristics of left ventricular thrombus: a comparison of contrast-enhanced magnetic resonance imaging, transthoracic echocardiography, and transesophageal echocardiography with surgical or pathological validation. Am Heart J. 2006;152(1):75–84. 27. Mahrholdt H, et al. Delayed enhancement cardiovascular magnetic resonance assessment of non-ischaemic cardiomyopathies. Eur Heart J. 2005;26(15):1461–1474. 28. Kim RJ, et al. Relationship of MRI delayed contrast enhancement to irreversible injury, infarct age, and contractile function. Circulation. 1999;100(19):1992–2002. 29. Reimer KA, Jennings RB. The changing anatomic reference base of evolving myocardial infarction. Underestimation of myocardial collateral blood flow and overestimation of experimental anatomic infarct size due to tissue edema, hemorrhage and acute inflammation. Circulation. 1979;60(4):866–876. 30. Willerson JT, et al. Abnormal myocardial fluid retention as an early manifestation of ischemic injury. Am J Pathol. 1977;87(1):159–188. 31. Higgins CB, et al. Nuclear magnetic resonance imaging of acute myocardial infarction in dogs: alterations in magnetic relaxation times. Am J Cardiol. 1983;52(1):184–188. 32. McNamara MT, et al. Detection and characterization of acute myocardial infarction in man with use of gated magnetic resonance. Circulation. 1985;71(4):717–724. 33. Friedrich MG. Tissue characterization of acute myocardial infarction and myocarditis by cardiac magnetic resonance. J Am Coll Cardiol Imag. 2008;1:652–662. 34. Marie PY, et al. Detection and prediction of acute heart transplant rejection with the myocardial T2 determination provided by a blackblood magnetic resonance imaging sequence. J Am Coll Cardiol. 2001;37(3):825–831. 35. Abdel-Aty H, et al. Edema as a very early marker for acute myocardial ischemia: a cardiovascular magnetic resonance study. J Am Coll Cardiol. 2009;53(14):1194–1201.

Multimodality Imaging in Cardiovascular Medicine

36. Abdel-Aty H, et al. Delayed enhancement and T2-weighted cardiovascular magnetic resonance imaging differentiate acute from chronic myocardial infarction. Circulation. 2004;109(20):2411–2416. 37. Abdel-Aty H, Simonetti O, Friedrich MG. T2-weighted cardiovascular magnetic resonance imaging. J Magn Reson Imaging. 2007;26(3):452–459. 38. Sharkey SW, et al. Acute and reversible cardiomyopathy provoked by stress in women from the United States. Circulation. 2005;111(4):472–479. 39. Friedrich MG, et al. Contrast media-enhanced magnetic resonance imaging visualizes myocardial changes in the course of viral myocarditis. Circulation. 1998;97(18):1802–1809. 40. Mahrholdt H, et al. Cardiovascular magnetic resonance assessment of human myocarditis: a comparison to histology and molecular pathology. Circulation. 2004;109(10):1250–1258. 41. Aletras AH, et al. Retrospective determination of the area at risk for reperfused acute myocardial infarction with T2-weighted cardiac magnetic resonance imaging: histopathological and displacement encoding with stimulated echoes (DENSE) functional validations. Circulation. 2006;113(15):1865–1870. 42. Dymarkowski S, et al. Value of t2-weighted magnetic resonance imaging early after myocardial infarction in dogs: comparison with bis-gadolinium-mesoporphyrin enhanced T1-weighted magnetic resonance imaging and functional data from cine magnetic resonance imaging. Invest Radiol. 2002;37(2):77–85. 43. Nilsson JC, et al. Sustained postinfarction myocardial oedema in humans visualised by magnetic resonance imaging. Heart. 2001;85(6):639–642. 44. Schulz-Menger J, et al. Cardiovascular magnetic resonance of acute myocardial infarction at a very early stage. J Am Coll Cardiol. 2003;42(3):513–518. 45. Friedrich MG, et al. The salvaged area at risk in reperfused acute myocardial infarction as visualized by cardiovascular magnetic resonance. J Am Coll Cardiol. 2008;51(16):1581–1587. 46. Stork A, et al. Comparison of an edema-sensitive HASTE-TIRM sequence with delayed contrast enhancement in acute myocardial infarcts. Rofo. 2003;175(2):194–198. 47. Mahrholdt H, et al. Reproducibility of chronic infarct size measurement by contrast-enhanced magnetic resonance imaging. Circulation. 2002;106(18):2322–2327. 48. Wagner A, et al. Contrast-enhanced MRI and routine single photon emission computed tomography (SPECT) perfusion imaging for detection of subendocardial myocardial infarcts: an imaging study. Lancet. 2003;361(9355):374–379. 49. Pennell D. Myocardial salvage: retrospection, resolution, and radio waves. Circulation. 2006;113(15):1821–1823. 50. Choi KM, et al. Transmural extent of acute myocardial infarction predicts long-term improvement in contractile function. Circulation. 2001;104(10):1101–1107. 51. Pfeffer MA, Braunwald E. Ventricular remodeling after myocardial infarction. Experimental observations and clinical implications. Circulation. 1990;81(4):1161–1172. 52. Basso C, et al. Morphologic validation of reperfused hemorrhagic myocardial infarction by cardiovascular magnetic resonance. Am J Cardiol. 2007;100(8):1322–1327. 53. Porto I, et al. Relation of myocardial blush grade to microvascular perfusion and myocardial infarct size after primary or rescue percutaneous coronary intervention. Am J Cardiol. 2007;99(12):1671–1673. 54. Wu KC, et al. Prognostic significance of microvascular obstruction by magnetic resonance imaging in patients with acute myocardial infarction. Circulation. 1998;97(8):765–772. 55. Hombach V, et al. Sequelae of acute myocardial infarction regarding cardiac structure and function and their prognostic significance as assessed by magnetic resonance imaging. Eur Heart J. 2005;26(6):549–557. 56. Shiga T, et al. Diagnostic accuracy of transesophageal echocardiography, helical computed tomography, and magnetic resonance imaging for suspected thoracic aortic dissection: systematic review and meta-analysis. Arch Intern Med. 2006;166(13):1350–1356.

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57. Schoepf UJ, Goldhaber SZ, Costello P. Spiral computed tomography for acute pulmonary embolism. Circulation. 2004;109(18): 2160–2167. 58. Gosalia A, et al. CT detection of acute myocardial infarction. AJR Am J Roentgenol. 2004;182(6):1563–1566. 59. Lessick J, et al. Diagnostic accuracy of myocardial hypoenhancement on multidetector computed tomography in identifying myocardial infarction in patients admitted with acute chest pain syndrome. J Comput Assist Tomogr. 2007;31(5):780–788. 60. Gerber BL, et al. Characterization of acute and chronic myocardial infarcts by multidetector computed tomography: comparison with contrast-enhanced magnetic resonance. Circulation. 2006;113(6):823–833. 61. Baks T, et al. Multislice computed tomography and magnetic resonance imaging for the assessment of reperfused acute myocardial infarction. J Am Coll Cardiol. 2006;48(1):144–152. 62. Lardo AC, et al. Contrast-enhanced multidetector computed tomography viability imaging after myocardial infarction: characterization of myocyte death, microvascular obstruction, and chronic scar. Circulation. 2006;113(3):394–404. 63. Nieman K, et al. Reperfused myocardial infarction: contrastenhanced 64-section CT in comparison to MR imaging. Radiology. 2008;247(1):49–56. 64. Habis M, et al. Acute myocardial infarction early viability assessment by 64-slice computed tomography immediately after coronary angiography: comparison with low-dose dobutamine echocardiography. J Am Coll Cardiol. 2007;49(11):1178–1185. 65. Sato A, et al. Early validation study of 64-slice multidetector computed tomography for the assessment of myocardial viability and the prediction of left ventricular remodelling after acute myocardial infarction. Eur Heart J. 2008;29(4):490–498. 66. Herzog BA, et al. Accuracy of low-dose computed tomography coronary angiography using prospective electrocardiogram-triggering: first clinical experience. Eur Heart J. 2008;29(24):3037–3042. 67. Husmann L, et al. Feasibility of low-dose coronary CT angiography: first experience with prospective ECG-gating. Eur Heart J. 2008;29(2):191–197. 68. Steigner ML, et al. Narrowing the phase window width in prospectively ECG-gated single heart beat 320-detector row coronary CT angiography. Int J Cardiovasc Imaging. 2009;25(1):85–90. 69. Maruyama T, et al. Radiation dose reduction and coronary assessability of prospective electrocardiogram-gated computed tomography coronary angiography: comparison with retrospective electrocardiogram-gated helical scan. J Am Coll Cardiol. 2008;52(18):1450–1455. 70. Khaw BA. The current role of infarct avid imaging. Semin Nucl Med.1999;29(3):259–270. 71. Flotats A, Carrio I. Non-invasive in vivo imaging of myocardial apoptosis and necrosis. Eur J Nucl Med Mol Imaging. 2003;30(4):615–630. 72. Okada RD, et al. Myocardial kinetics of technetium-99m-hexakis-2methoxy-2-methylpropyl-isonitrile. Circulation. 1988;77(2):491–498. 73. Heller GV, et al. Clinical value of acute rest technetium-99m tetrofosmin tomographic myocardial perfusion imaging in patients with

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acute chest pain and nondiagnostic electrocardiograms. J Am Coll Cardiol. 1998;31(5):1011–1017. 74. Kontos MC, et al. Comparison of myocardial perfusion imaging and cardiac troponin I in patients admitted to the emergency department with chest pain. Circulation. 1999;99(16):2073–2078. 75. Varetto T, et al. Emergency room technetium-99m sestamibi imaging to rule out acute myocardial ischemic events in patients with nondiagnostic electrocardiograms. J Am Coll Cardiol. 1993;22(7):1804–1808. 76. Klocke FJ, et al. ACC/AHA/ASNC guidelines for the clinical use of cardiac radionuclide imaging—executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/ASNC Committee to Revise the 1995 Guidelines for the Clinical Use of Cardiac Radionuclide Imaging). Circulation. 2003;108(11):1404–1418. 77. Gibbons RJ, et al. The quantification of infarct size. J Am Coll Cardiol. 2004;44(8):1533–1542. 78. Gibbons RJ, et al. Myocardium at risk and infarct size after thrombolytic therapy for acute myocardial infarction: implications for the design of randomized trials of acute intervention. J Am Coll Cardiol. 1994;24(3):616–623. 79. Dakik HA, et al. Assessment of myocardial viability with 99mTcsestamibi tomography before coronary bypass graft surgery: correlation with histopathology and postoperative improvement in cardiac function. Circulation. 1997;96(9):2892–2898. 80. Medrano R, et al. Assessment of myocardial viability with 99mTc sestamibi in patients undergoing cardiac transplantation. A scintigraphic/pathological study. Circulation. 1996;94(5):1010–1017. 81. Christian TF, et al. Relation of left ventricular volume and function over one year after acute myocardial infarction to infarct size determined by technetium-99m sestamibi. Am J Cardiol. 1991;68(1):21–26. 82. Christian TF, et al. Mismatch of left ventricular function and infarct size demonstrated by technetium-99m isonitrile imaging after reperfusion therapy for acute myocardial infarction: identification of myocardial stunning and hyperkinesia. J Am Coll Cardiol. 1990;16(7):1632–1638. 83. Behrenbeck T, et al. Primary angioplasty in myocardial infarction: assessment of improved myocardial perfusion with technetium-99m isonitrile. J Am Coll Cardiol. 1991;17(2):365–372. 84. Miller TD, et al. Infarct size after acute myocardial infarction measured by quantitative tomographic 99mTc sestamibi imaging predicts subsequent mortality. Circulation. 1995;92(3):334–341. 85. Burns RJ, et al. The relationships of left ventricular ejection fraction, end-systolic volume index and infarct size to six-month mortality after hospital discharge following myocardial infarction treated by thrombolysis. J Am Coll Cardiol. 2002;39(1):30–36. 86. Miller TD, et al. Usefulness of technetium-99m sestamibi infarct size in predicting posthospital mortality following acute myocardial infarction. Am J Cardiol. 1998;81(12):1491–1493. 87. Ndrepepa G, et al. Prognostic value of myocardial salvage achieved by reperfusion therapy in patients with acute myocardial infarction. J Nucl Med. 2004;45(5):725–729.

4

Noninvasive Imaging in Patients With Suspected Unstable Angina or Non-ST Elevation MyocardialÂ€Infarction

Benjamin W. Kron Ke vin Wei

Each year in the United States, over 5 million patients present to emergency departments (EDs) complaining of chest pain (CP). The cause of these symptoms may range from benign musculoskeletal problems to life-threatening conditions such as acute myocardial infarction (AMI), aortic dissection, or acute pulmonary embolism. Although most patients end up having minor causes of CP, the significant morbidity and mortality associated with these latter conditions and the inability of physicians to definitively exclude those using simple bedside tools results in most of these patients undergoing prolonged observation and extensive workups prior to discharge. Because of the difficulty in establishing or excluding the presence of a severe cause for a patient’s CP, much attention has been focused on the use of ancillary noninvasive imaging to assist in the triage and risk stratification of these patients. Of the serious causes of CP noted above, cardiac CP is the most frequent [1–3]. An acute coronary syndrome (ACS) is the result of myocardial ischemia (a lack of blood flow to the heart resulting in tissue hypoxia) and encompasses a wide spectrum of presentations from unstable angina (UA) to ST elevation myocardial infarction (STEMI). Patients with new left bundle branch block on the 12-lead electrocardiogram (ECG), 0.2 mV ST elevation in anteroseptal leads, or 0.1 mV elevation in other leads can be classified as STEMI and are candidates for immediate reperfusion therapy with fibrinolysis or percutaneous coronary intervention [4]. Ancillary imaging is not required in such patients to make a diagnosis and should not be considered in order to facilitate urgent reperfusion. Unfortunately, the majority of patients with an ACS do not present as a STEMI. In a study of 3814 patients presenting with CP to the ED, 93% of the presenting ECGs were called normal or nondiagnostic. In those patients whose presenting ECG showed only early 58

repolarization, nondiagnostic changes, or was normal, the rate of death, AMI, or revascularization at 30 days was as high as 23% [5]. Thus, a benign ECG at the time of presentation does not confer a good prognosis. The history, physical examination, ECG, and serum cardiac biomarkers are currently the main tools used to determine if a patient is presenting with an ACS. These findings are also used to provide initial risk stratification. Features that suggest a high likelihood of ACS include patients whose presenting symptoms are similar to previously documented angina, especially in those with a known history of coronary disease or prior myocardial infarction, findings on examination of hemodynamic compromise or heart failure, ECG abnormalities such as new or dynamic ST segment depression or deep T-wave inversion, or elevated serum cardiac biomarkers [6]. Most patients in whom a definitive diagnosis of ACS is established also do not generally require noninvasive imaging and should be managed according to published guidelines. The majority of patients presenting with an ACS, however, lack the symptoms or ECG findings noted above. Elevated levels of cardiac biomarkers are the gold standard for determining the presence of myocellular necrosis, but their kinetics of release into the serum makes them insensitive until many hours after the onset of symptoms [7]. Single determinations of creatinine kinase (CK) at the time of patient presentation have a sensitivity of only 36% for detecting AMI. The sensitivity increases to 69% at 4 hours, and to 95% to 99% by 15 hours [7]. Likewise, cardiac troponins and myoglobin also have limited sensitivity early after the onset of ischemia. Because of the time-dependent nature of ACS, this delay in the diagnosis and risk stratification of patients may worsen their outcome because definitive treatment is not initiated promptly. Serum cardiac biomarker release is also not specific for ischemic injury and may be abnormally elevated in myocarditis, congestive heart failure, or increased myocardial demand [8–10]. Thus, physicians still depend on unreliable parameters such as a patient’s presenting symptoms and physical findings to determine if they have an ACS.

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Noninvasive Imaging in Patients With Suspected Unstable Angina or Non-ST Elevation Myocardial Infarction

Because the diagnosis or exclusion of an ACS is difficult, the current process is often prolonged and requires monitoring in an ED, CP center, or step-down unit, with repeated sets of blood work for cardiac serum markers. It has been estimated that the cost of excluding ACS in patients with CP is between 8 and 10 billion dollars annually in the United States alone. Despite these huge resources, up to 11% of patients are inadvertently discharged from the ED with a missed AMI (average 2.1%), and UAP is missed in up to 4% [11–13]. This misdiagnosis and inappropriate discharge leads to increased mortality for those patients who have an AMI outside the hospital [13]. A diagnostic tool that could improve our ability to detect or exclude ACS in patients with CP but without definitive ECG changes (ST elevation, ST depression, or deep T inversions on the initial ECG), or elevated cardiac serum markers, would therefore be invaluable. In recent years, 2-dimensional (2D) echocardiography, single photon emission computed tomography (SPECT), cardiac magnetic resonance imaging (CMR), and multidetector computed tomography (MDCT) have been evaluated for this purpose.

jâ•…PATHOPHYSIOLOGY OF ACSS AND IMPLICATIONS FOR IMAGING Due to the autoregulatory capacity of the coronary microcirculation, resting myocardial blood flow (MBF) remains constant over a wide range of coronary driving pressures [14]. Consequently, MBF does not fall below normal resting levels until a coronary obstruction exceeds 85% to 90% of the luminal area of an epicardial coronary artery [15]. With such critical stenoses, supply-demand mismatch can result in angina occurring at rest, which is 1 of the 3 principal presentations of UA [6]. Other manifestations of UA include accelerated angina (increased frequency, duration, or onset at a lower threshold) or new-onset angina of at least Canadian Cardiovascular Class III severity [16]. The coronary lesion most commonly associated with the development of an ACS is characterized by erosion or disruption of an atherosclerotic plaque, which brings about a series of pathological processes that decrease MBF. Early atherosclerotic lesions demonstrate upregulation of adhesion molecules on the endothelial cell surface [17], resulting in infiltration of inflammatory cells into the arterial wall. Once there, monocytes develop into macrophages as they ingest oxidized low-density lipoprotein and differentiate into foam cells. Macrophages and lipid-laden foam cells produce cytokines that weaken the fibrous cap of an atherosclerotic lesion through inhibition of collagen production by smooth muscle cells, as well as from the production of matrix metalloproteinases, which degrade collagen [18]. Destabilization of the fibrous plaque and plaque rupture result in exposure of the necrotic lipid core to circulating blood, with resultant thrombus formation. The development

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of a thrombus, which is usually nonocclusive, but is critical enough to reduce resting MBF or severely limit coronary flow reserve leads to an ACS. UA and non-ST elevation MI (NSTEMI) share the same pathophysiology and are part of a continuum, with NSTEMI being a more serious manifestation of the process. An NSTEMI is associated with myocardial injury that will cause the release of detectable quantities of biomarkers. If no biomarker has been released, indicating necrosis, the patient is determined to have UA [6]. There are a number of other pathophysiological mechanisms that can lead to UA and NSTEMI, which are less common than plaque rupture and acute thrombosis. Intense focal spasm of a segment of an epicardial coronary artery caused by endothelial dysfunction and/or hypercontractility of vascular smooth muscle can result in an ACS. Large-vessel spasm can occur on top of nonobstructive plaque as well. Resting perfusion can also be compromised by the development of a coronary artery dissection. Lastly, there is secondary UA, where the precipitating condition is extrinsic to the coronary arterial bed. Patients with secondary UA often have chronic stable angina with an underlying coronary atherosclerotic narrowing, which results in partial exhaustion of coronary vasodilatory reserve. Secondary UA can then be precipitated by conditions that cause an increase in myocardial oxygen requirements, such as tachycardia, severe hypertension, hyperthyroidism, anemia, and so forth.

jâ•…I MAGING METH ODS FOR DETECTION OF ACSS Based on the pathophysiology outlined above, noninvasive imaging techniques have focused on the detection of either anatomically significant coronary artery disease (CAD), reduced perfusion to myocytes, or the consequences of abnormal perfusion (eg, abnormal cardiac function) in order to detect UA or NSTEMI.

jâ•…A SSESSMENT OF WALL THICKENING 2D echocardiography, CMR, computed tomography (CT), and gated SPECT can all be used to evaluate wall thickening (WT), which is closely dependent on resting MBF. Because myocardial contractility is a major determinant of myocardial oxygen consumption, reductions in resting MBF are followed within seconds by the development of hypokinesis. Figure 4.1 illustrates the close coupling that exists between resting MBF and WT [19]. Normal resting MBF (1 mL/kg/min) is associated with WT of approximately 30%. With acute reductions in resting MBF, WT abnormalities develop within seconds. Thus, the assessment of WT provides an indirect measure of the presence of myocardial ischemia.

6 0 Multimodality Imaging in Cardiovascular Medicine

F igure 4 . 1 â•…Relation between resting myocardial blood flow (MF) and wall thickening. Adapted from Ref. 19.

F igure 4 . 2 â•…Relation between myocardial blood flow (MBF) and myocardial uptake of nuclear tracers. Adapted from Ref. 25.

In patients who suffer only transient ischemia, even a brief coronary occlusion (5–15 minutes) results in severely reduced regional systolic function [19]. These functional changes occur briskly and are evident for hours after the initial insult, despite reperfusion, and may take up to 48 hours to normalize [20–22]. The duration and severity of systolic dysfunction (myocardial stunning) directly relate to the duration of ischemic insult, severity of the insult, and the adequacy of reperfusion [20–22].

a contrast agent bolus, ischemic myocardium will demonstrate slow wash-in of contrast and relative hypoperfusion compared to normally perfused tissue [27]. As shown in Figure 4.4, the excellent spatial resolution of CMR can easily delineate the subendocardial location of such defects. The contrast agents that now enable perfusion imaging during echocardiography are composed of microbubbles of high–molecular weight gas (mainly perfluorocarbons currently), encapsulated within a thin shell. Within an ultrasound field, nonlinear oscillation and destruction of microbubbles produces signals that are unique from myocardial tissue. These signals can be selectively received by novel imaging modalities designed specifically for myocardial contrast echocardiography (MCE). Unlike the contrast agents used with CT, CMR, or SPECT, microbubbles remain entirely intravascular, are hemodynamically inert, and have a microvascular rheology identical to that of red blood cells. These properties make microbubbles unique perfusion agents and obviate the need for complex modeling that is required with many other technologies for

jâ•…M YOCARDIAL PERFUSION IMAGING Perfusion imaging with SPECT most often utilizes thallium 201 or 99mTechnetium (99mTc). Thallium 201 is a potassium analog with myocardial uptake that is partly dependent on the Na-K-ATPase pump and is directly proportional to MBF [23]. Following its uptake, there is continued exchange between the myocytes and the extracellular space, resulting in redistribution of thallium over time [23]. 99mTc-sestamibi and tetrofosmin are lipophilic monovalent cations that diffuse passively across plasma and mitochondrial membranes and are sequestered by the large negative membrane potential of mitochondria where they demonstrate no significant redistribution [24]. The relation between MBF and tracer uptake over a wide range of flow rates is shown in Figure 4.2. The uptake of an ideal tracer is completely linear over a wide range of flows (line C), while the uptake of thallium (line B) and 99m Tc-sestamibi (line A) plateau at hyperemic flows [25]. Both thallium and 99mTc-sestamibi, however, demonstrate uptake that is directly proportional to MBF when MBF is reduced below normal resting levels—similar to an ideal tracer [25]. Thus, injection of either tracer in a patient with CP should demonstrate perfusion defects if there is resting ischemia in the setting of an ACS (Figure 4.3). Perfusion CMR uses ultrafast, time-resolved T1-weighted data sets acquired during a bolus injection of gadolinium contrast [26]. Based on first-pass kinetics of

F igure 4 . 3 â•… Horizontal long-axis view of the left ventricle demonstrat-

ing a resting lateral defect (arrow) using emission computed tomography.

Tc-sestamibi single photon

99m

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F igure 4 . 4 â•… Short-axis cardiac magnetic resonance image demonstrating a subendocardial inferior defect (arrow).

quantifying MBF. During a continuous infusion, microbubbles within the myocardial microcirculation can be destroyed using high-power ultrasound, and their subsequent replenishment of tissue is dependent on MBF velocity. Ischemic myocardial segments with low resting flow demonstrate resting perfusion defects (Figure 4.5).

j â•…N ONINVASIVE CORONARY ANGIOGRAPHY Noninvasive assessment of the coronary arteries has been most successful using cardiovascular CT angiography (CCTA). The use of 64-slice MDCT scanners has

F igure 4 . 6 â•… Severe mid right coronary artery stenosis (arrow) detected using 64-slice multidetector computed tomography.

shown excellent accuracy for diagnosing CAD. Newer dual-source 64-slice MDCT and 256-slice detectors may Â�further improve temporal resolution and volume coverage, respectively [28]. Cardiac MDCT offers submillimeter isotropic resolution, typically in the range of 400 μm. A typical CCTA can be performed with 60 to 80 mL of contrast media and a breath-hold spell of ,10 seconds. In order to achieve high contrast enhancement in this short time, a contrast agent with a high concentration of iodine (eg, 370 mgI/mL) should be used, along with a test injection or automated threshold-based bolus to ensure proper timing [28]. A saline flush should be performed immediately after administration of contrast to maintain a tight contrast bolus and decrease the total volume of contrast that is needed for the study [29]. Figure 4.6 shows an example of a patient with suspected cardiac CP who was found to have a severe mid right coronary artery stenosis on CCTA.

jâ•…D IAGNOSTIC AND PROGNOSTIC UTILITY OF NONINVASIVE IMAGING FOR PATIENTS WITH SUSPECTED ACSS Echocardiography

F igure 4 . 5 â•…Apical 3-chamber view showing a dense resting perfusion defect involving the mid to apical septum (arrowheads) using harmonic power Doppler imaging and Definity.

As mentioned above, 2D echocardiography detects a new ACS based on the relationship between MBF and regional WT—a new regional wall motion abnormality is an early manifestation of ischemia. It has been shown that even after a brief coronary occlusion (5–15 minutes), regional systolic function is severely reduced [30]. These functional changes

62 Multimodality Imaging in Cardiovascular Medicine

occur briskly and are evident for hours after the initial insult, despite reperfusion, and may take up to 48 hours to normalize [30–34]. The duration and severity of systolic dysfunction directly relates to the duration of ischemic insult, severity of the insult, and the adequacy of reperfusion [31–35]. In order to have high sensitivity, it is of utmost importance to clearly visualize each myocardial segment, so the use of contrast agents for left ventricular endocardial border delineation is critical for this application of echocardiography. Furthermore, as noted below, myocardial perfusion imaging using MCE can provide incremental prognostic utility. Several studies have evaluated MCE in the evaluation of patients presenting with CP but no ST elevation in the ED. A multicenter, prospective study compared MCE and SPECT to diagnose AMI and risk stratify 203 patients for the development of hard cardiovascular end points (AMI, urgent revascularization, or death) within 48 hours [36]. MCE was found to be equivalent to SPECT in Â�diagnosing AMI but was inferior with respect to predicting other adverse cardiac events. Both MCE and SPECT added significant additional information (17% and 23.5%, respectively) for diagnosis and short-term prognosis over routine clinical methods (ECG, history, and risk factors). This study demonstrated for the first time the incremental value of MCE in the diagnosis and short-term prognosis of AMI. The assessment of myocardial perfusion played a dominant role in the value of MCE. Surprisingly, the evaluation of regional function (RF) was less powerful. The use of bolus administration of the microbubble contrast agent could have resulted in far-field attenuation and affected the assessment of RF. Additionally, UA was not included as an end point, which may have underestimated the diagnostic and prognostic capabilities of MCE in this study. Both wall motion and perfusion with MCE were used to evaluate 100 patients with first-time CP to demonstrate the ability of MCE to detect ACSs (UA, NSTEMI) compared to traditional clinical tests [37]. Those with ST elevation, known CAD, or previous myocardial infarction were excluded. Contrast agents were administered as a slow bolus, and MCE was performed using low mechanical index real-time imaging. Thirty-seven patients were diagnosed with an ACS. An abnormal MCE exam was the most powerful predictor of an ACS (89% sensitivity, 93% specificity, P , .001). Myocardial perfusion was superior to wall motion analysis for detecting an ACS. In 21 patients, MCE was performed before the initial troponin data were available, and 95/98 underwent MCE before follow-up troponins were performed—MCE can thus identify high-risk patients more quickly than the use of serum cardiac markers. In 2 patients with abnormal troponin values, MCE was found to be normal but identified the presence of pericardial Â�effusions. Subsequent angiography was also normal and these individuals were diagnosed with perimyocarditis— demonstrating the excellent negative predictive value of MCE. The use of MCE further strengthened the findings in a prospective study of 114 patients presenting to the

emergency room with suspected cardiac CP [38]. The main study end point was the diagnosis of an ACS. Patients who had Q waves on ECG or a history of myocardial infarction were excluded. All patients underwent MCE and coronary angiography in addition to ECG and serologic testing. Microbubbles were administered using a more contemporary continuous infusion method. An ACS was diagnosed in 87 patients. Myocardial perfusion defects demonstrated 77% sensitivity for the detection of ACS compared to 28% and 34%, respectively, with ECG and troponin, while maintaining similar specificity (89%–96%). Abnormal myocardial perfusion was the only independent variable for diagnosing an ACS (odds ratio 87, P , .001). RF was not as powerful as perfusion for predicting an ACS, but was more sensitive than ST changes or troponin alone (65% compared to 33% and 54%, respectively). This study similarly found incremental benefits for MCE over ECG and cardiac biomarkers in the setting of suspected cardiac CP. The largest study to date evaluating MCE in patients with CP included 1017 patients presenting to the ED who were .30 years of age, with CP lasting at least 30 minutes occurring within the previous 12 hours. Primary end points included all-cause mortality and acute MI. Secondary end points included revascularization or UA (typical CP, dynamic ECG changes, and/or mild troponin elevation). Late prognostic utility was also evaluated and patients were followed up for up to 2 years. MCE was performed with a continuous infusion of microbubbles, and images were interpreted separately for RF and myocardial perfusion by experienced clinicians blinded to all clinical information. In contradistinction to the last few studies presented, patients with a prior MI were not excluded from enrollment. The short-term and long-term prognostic significance of MCE on primary and secondary cardiovascular end points were determined in the study from Rinkevich et al [39]. Total short-term events (48 hours) were noted in 16% of patients, 9% of whom had AMI. Patients with abnormal RF were 6-fold more likely to have an early event compared to those with normal function. Patients with abnormal perfusion were 2.5-fold more likely to have an adverse event, but those with both abnormal RF and myocardial perfusion were 14.3-fold (P , .001) more likely to have events, demonstrating the incremental benefit of combined WT and perfusion data over RF alone in these patients. Similar findings were noted over late follow-up where patients with abnormal RF had a 5-fold increased incidence of an adverse event compared to those with normal function, and the patients with both abnormal perfusion and function were at the highest risk of adverse events (10-fold increase). In clinical practice, it is important not only to diagnose an ACS, but to risk stratify patients appropriately for decisions regarding triage and management. A commonly used clinical tool is the thrombolysis in myocardial infarction (TIMI) risk score [40]. However, because there is an inherent delay in obtaining serum cardiac biomarker data, a full TIMI risk score cannot be derived in patients at the

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Noninvasive Imaging in Patients With Suspected Unstable Angina or Non-ST Elevation Myocardial Infarction

time of a patient’s presentation to the ED. MCE may therefore provide better risk stratification early in the assessment of CP patients than even a composite risk score. This hypothesis was evaluated by Tong et al [41]. Normal RF and perfusion on MCE were used to identify a low-risk population (adverse event rate of 0.4%) and were found to have a better negative predictive value than the TIMI score without troponins (2% adverse event rate in patients with a modified TIMI score of 0–1). As shown in Figure 4.7, even when patients are considered low risk by clinical criteria, MCE can further subdivide those patients into low-, Â�intermediate-, and high-risk groups based on their RF and myocardial perfusion findings. The same holds true for patients who are clinically intermediate risk (Figure 4.8). Although the ability of MCE to detect a patient with an ongoing ACS or AMI is excellent, RF and myocardial perfusion abnormalities may resolve in patients with only transient ischemia, especially if there is a significant delay between the

Event-Free Survival

1.0 Nl RF + MCE (n=350)

0.8

Ab RF + Nl MCE (n=91)

0.6

Ab RF + Ab MCE (n=85)

0.4

0.2

0.0

0

2

4

6

8

10

12

14

16

18

20

22

24

Follow-up(months) F igure 4 . 7 â•…Risk stratification of chest pain patients who are clinically low risk (modified thrombolysis in myocardial infarction score 0–2) based on results of contrast echocardiography. Nl, normal; Ab, abnormal; RF, regional function; MCE, myocardial contrast echocardiography. Adapted from Ref. 41.

1.0

Event-Free Survival

0.8

Nl RF + MCE (n=114)

0.6

Ab RF + Nl MCE (n=41)

0.4 Ab RF + MCE (n=87)

0.2

0.0

0

2

4

6

8

10

12

14

16

18

20

22

24

Follow-up(months) F igure 4 . 8 â•…Risk stratification of chest pain patients who are clinically intermediate risk (modified thrombolysis in myocardial infarction score 3–4) based on results of contrast echocardiography. Nl, normal; Ab, abnormal; RF, regional function; MCE, myocardial contrast echocardiography. Adapted from Ref. 41.

63

ischemic episode and imaging. The effect of the timing of MCE and patient presentation were evaluated in a study where the patients were divided into 4 quartiles (0, 1, 4, and 12 hours) based on their last episode of CP [42]. The negative predictive value of MCE was found to remain extremely high (94% for the development of any cardiac event) even up to 12 hours after CP had resolved [42]. Thus, even in the setting of Â�spontaneous reperfusion and restoration of normal antegrade flow, the presence of myocardial stunning in patients who have suffered significant ischemia persists for many hours. The cost associated with the performance of echocardiography (especially if contrast is used for every case) is substantial. It has been shown, though, that by reducing the number of unnecessary admissions to hospital and other downstream costs for low-risk patients, MCE is cost-efficient and can even reduce the costs of managing patients with undifferentiated CP by as much as $900 per patient [43]. One of the limitations of echocardiography is that the positive predictive value of MCE was found to be only 34% when patients with prior MI were not excluded, because the presence of existing wall motion abnormalities confounds their evaluation [42]. Since many patients have a history of prior cardiac events, it is unsatisfactory to exclude a significant proportion of patients from potentially beneficial technology. Another way to determine if an abnormality is new is to compare with a previous MCE study, but many patients do not have prior studies for comparison. In the future, it may be possible for microbubbles to detect specific molecular events within the circulation. In ischemiareperfusion injury, inflammation is prominent. By changing the surface of microbubbles, they can be made to stick and accumulate at sites of inflammation by attaching to upregulated molecules there. Specific targeted microbubbles have been developed with robust attachment to activated leukocytes, or even to the endothelial surface itself. Strategies that have been used include the addition of phosphatidylserine to the lipid shell to increase complement deposition [44] or the conjugation of specific ligands (such as monoclonal antibodies or peptides) to the microbubble surface [45,46]. This technique has been used to specifically image the molecular mediators of leukocyte recruitment such as the selectins, ICAM-1, VCAM-1, and MAdCAM-1. The ability of MCE to detect regional Â�myocardial Â�inflammation was tested in an animal Â�experimental model of left anterior descending coronary artery occlusion for 90 Â�minutes followed by reperfusion [44]. Phosphatidylserinelipid–shelled microbubbles targeted to activated leukocytes were injected 60 minutes after reperfusion followed by imaging 15 Â�minutes later. Figure 4.9 shows the MCE images (Panel A), and a 2,3,5- Â�triphenyltetrazolium chloride–stained slice of Â�myocardium (to delineate infarction, panel B). The short-axis background-subtracted color-coded MCE image demonstrates an area of contrast enhancement (green and red) from retained targeted microbubbles. The location and spatial extent of inflammation on MCE includes not only the area of Â�myocardial Â�necrosis (panel B) but also

6 4 Multimodality Imaging in Cardiovascular Medicine

F igure 4 . 9 â•…Myocardial contrast echocardiography using microbubbles targeted to P-selectin (panel A, yellow arrowheads), and the corresponding triphenyltetrazolium– stained myocardium denoting subendocardial infarction (panel B, black arrowheads). Adapted from Ref. 44.

the surrounding ischemic myocardium that was salvaged by reperfusion. Even up to 120 Â�minutes after reperfusion, such MCE images of ischemic memory should be able to define the presence of recent ischemia, but significant delays between the event and imaging may limit the sensitivity of even MCE. Such issues still require further study. Real-time 3D echocardiography is an emerging technique that has the potential to enhance cardiac functional assessment [47,48]. 2D echocardiography and MCE can be limited by the inability to visualize all wall segments, and the necessity of mentally reconstructing multiple images in the 2D plane. 3D echocardiography makes it possible to instantly obtain 3D imaging of the heart. This technique ensures identification of all wall segments and is potentially more sensitive in identifying small wall motion abnormalities. The role of 3D echo and its benefits over MCE have not been evaluated in patients with CP. Some advantages of MCE over other potential modalities are its cost, its speed, and its transportability. It is smaller and portable, compared to SPECT, CMR, and CT. Echo is also relatively cheap compared to these other Â�methods. No image processing is required. Limitations would include Â�operator-dependent image quality, lack of Â�quantitative Â�variables for evaluation, and inadequate acoustic Â�windows in some patients despite using contrast. In the last year, the safety of ultrasound contrast agents was brought into Â�question by the US Food and Drug Administration (FDA). A number of large database reviews have now shown that ultrasound contrast agents are extremely safe, even in critically ill patients [49,50]. Currently, the FDA still recommends 30 minutes of observation with ECG and O2 saturation monitoring in acutely ill patients who have received ultrasound contrast agents. Single Photon Emission Computed Tomography Because SPECT relies on the principal that a reduction in resting MBF is associated with a proportionate decrease in the uptake of nuclear perfusion tracers, the detection of acute cardiac

ischemia with this technique makes pathophysiologic sense. With 99mTc-based agents, patients can be imaged at a later time point after injection, because the lack of redistribution after initial injection still reflects MBF at the time of injection. Therefore, this technique provides an assessment of reduced resting MBF, through detection of these tracers. Reduced resting MBF is the underlying cause of myocardial ischemia so this technique effectively evaluates myocardial ischemia. Table 4.1 shows a list of studies utilizing nuclear imaging in patients with CP, along with their overall sensitivity, specificity, and negative predictive value for diagnosing AMI in the ED [51–57]. The sensitivity for detecting AMI ranged from 90% to 100% with negative predictive values of 99% to 100%. The limited specificity is a result of an inability of 99mTc-SPECT to distinguish between new and old infarctions. Although the studies above confirmed the diagnostic potential of SPECT, they did not address the impact of SPECT on clinical decision making. This issue was evaluated in a large randomized study where patients were randomized to either usual care or a scan strategy that incorporated results derived from immediate resting 99m Tc-SPECT perfusion imaging [57]. All patients presented with symptoms suggestive of acute cardiac ischemia within 3 hours of consent and had a normal or nondiagnostic initial ECG. In patients eventually diagnosed with ACS, there was no difference in appropriate hospital admission rates between the 2 groups. However, in patients without ACS, the number of unnecessary admissions to the CCU, telemetry ward, or CP unit was reduced from 52% to 42% (20% relative reduction, P , .001) [57]. SPECT was also found to risk stratify patients appropriately in this study—the incidence of AMI was 0.6%, 0.8%, and 10.3% in patients with normal, equivocal, and abnormal scans, respectively [57]. In addition to detecting perfusion defects, 99mTcsestamibi SPECT using gated acquisition and reconstruction have the added advantage of assessing regional and global ventricular functions [58,59]. The evaluation of ventricular function also provides prognostic as well as diagnostic information in patients. A multicenter study showed that the evaluation of wall motion and perfusion together

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65

jâ•… Table 4.1â•…Nuclear imaging in patients presenting to the emergency department with chest pain and a nondiagnostic ECG Study

Agent

N

Sensitivity (%)

Specificity (%)

NPV (%)

End Point

Varetto et al [51]

MIBI

â•‡â•‡ 62

100

92

100

CAD

Hilton et al [52]

MIBI

â•‡ 102

â•‡ 94

83

â•‡ 99

CAD/AMI

Tatum et al [53]

MIBI

â•‡ 438

100

78

100

AMI

Kontos et al [54]

MIBI

â•‡ 532

â•‡ 93

71

â•‡ 99

AMI

Heller et al [55]

Tetrofosmin

â•‡ 357

â•‡ 90

60

â•‡ 99

AMI

Kontos et al [56]

MIBI

â•‡ 620

â•‡ 92

67

â•‡ 99

AMI

Udelson et al [57]

MIBI

1215

â•‡ 96

–

â•‡ 99

AMI

AMI, acute myocardial infarction; CAD, coronary artery disease; ECG, electrocardiogram; MIBI, 99mTc-sestamibi; Tetrofosmin, 99mTc-tetrofosmin; NPV, negative Â�predictive value.

provided greater diagnostic and prognostic value than perfusion alone [60]. Their data showed that patients who had both abnormal wall motion and perfusion defects were significantly more likely to have an AMI compared to those with perfusion defects alone. Although SPECT is an expensive technology, the use of SPECT in patients with acute CP in the ED could be cost effective. Similar to echo, if SPECT imaging leads to a patient not needing to be admitted, this will ultimately save money. As discussed above, the high negative predictive value of SPECT allows the identification of low-risk patients with noncardiac CP and results in a higher rate of direct discharge from the ED. It has been estimated that despite the added cost of imaging in all patients with CP, there can be an average reduction of costs of $70 per patient [61]. There are limitations of SPECT as well. Most of the studies enrolled mainly low-risk patients with a low incidence of events in this population, and so estimating the negative predictive value of SPECT may be overoptimistic. Secondly, most of these studies used CK or CK-MB as the gold standard for diagnosis of AMI rather than the more sensitive cardiac troponins. It is known that around 3% to 4% of the left ventricular myocardium must be ischemic for a perfusion defect to appear on SPECT [58]; thus, smaller ischemic events detectable only with troponins may not be detected by SPECT, making sensitivity lower. One study showed normal SPECT perfusion in 34% of CP patients who were eventually diagnosed with an ACS [55]. This study highlighted the limited ability of SPECT to detect UA and milder ischemic events that are troponin positive but CK-MB negative. Some of these milder events, however, may be detectable using abnormal WT from gated SPECT [60]. SPECT has many obvious advantages such as timetested durability, high sensitivity, combined benefits of evaluating both perfusion and ventricular function, standardized

imaging protocols, and well-established quantitative methods. From a logistic standpoint, though, an expert panel recently outlined the difficulties of nuclear perfusion imaging, which included decay and license issues, the need for isotope preparation, relative inaccessibility of nuclear laboratories in many hospitals, difficulties with single-image interpretation rather than the usual stress/rest images for comparison, and low spatial resolution [62]. Ongoing developments in nuclear imaging may continue to address some of the limitations currently associated with imaging for the detection of ACS. For example, many patients continue to present to the ED late after their onset of CP. The detection of myocardial ischemia may not be possible with the assessment of MP if spontaneous reperfusion and restoration of normal MBF has occurred, or with RF if stunning has resolved. In the setting of Â�myocardial ischemia, however, the myocardium shifts high-energy ATP production from fatty acid metabolism (which is the preferred metabolic pathway) to glucose utilization [63]. Studies have shown that imaging of an iodinated fatty acid analog, 15-(p-[iodine-123]iodophenylÂ� -3-(R,S)Â�methylpentadecanoic acid (BMIPP) using SPECT can identify previous severe ischemia as areas of reduced tracer uptake. BMIPP is trapped in cardiomyocytes with limited catabolism [64] and can be imaged clinically with labeling using 123I. Myocardial uptake of BMIPP after an ischemic insult is diminished due to reduced activation of fatty acids by coenzyme A and less fatty acid metabolism [63]. The ability of BMIPP SPECT to identify recent Â�ischemia in patients presenting with CP was evaluated in 111 patients [65]. BMIPP SPECT was performed 1 to 5 days after the disappearance of the last episode of CP. Abnormal BMIPP had greater sensitivity than tetrofosmin SPECT for identifying patients with ischemia due to fixed CAD, or vasomotor spasm. Thus, ischemic memory imaging may be one method of identifying patients with acute

6 6 Multimodality Imaging in Cardiovascular Medicine

cardiac causes of CP but no MI. It may also be a method that allows the differentiation of acute ischemia from remote events in the same patient. Cardiac Magnetic Resonance Imaging CMR has recently shown promising results in the evaluation of patients with CP. This technology does not expose the patient to ionizing radiation or iodinated contrast agents and has excellent spatial and temporal resolution, as well as intrinsic blood-tissue delineation without the need for administration of an exogenous agent, thus allowing the evaluation of global and regional wall motion abnormalities [66]. Valve structure and function, as well as regurgitant lesions can be assessed with dynamic cine (bright blood) imaging, and the severity of regurgitation can be semiquantitatively assessed from jet appearance or quantified volumetrically using velocity phase maps [67]. GadoliniumDTPA can be utilized to assess myocardial perfusion, and the introduction of delayed enhancement can determine the presence of viable versus infarcted myocardium [68–70]. The spatial distribution of delayed enhancement may also assist in differentiating ischemic heart disease from other cardiac pathologies. Newer pulse sequences (T2 fast spin echo) allow imaging of myocardial edema, which is particularly useful when evaluating patients with acute CP. The presence of myocardial edema in a patient presenting with acute CP is highly suggestive of ACS [71]. Although not as advanced in development as MDCT, magnetic resonance angiography can assess proximal and mid coronary artery segments and exclude significant CAD [72]. A recent meta-analysis comparing CMR to MDCT showed MDCT to be superior to CMR in evaluating coronary anatomy; however, CMR still provides moderate results including a sensitivity of 72% and specificity of 87% when compared with angiography [72]. It is worth pointing out that as with MDCT, a number of the coronary segments evaluated with CMR were excluded because of motion artifact. Thus, CMR possesses many attributes that make it a potentially excellent method for assessment of patients with suspected ACS. The use of CMR in the acute setting of the ED to evaluate patients with CP has been less well studied than other modalities presented above. In one study, 161 CP patients presenting to the ED with a nondiagnostic ECG underwent CMR within 12 hours of presentation for evaluation of MP and RF. CMR was shown to have a sensitivity of 84% and a specificity of 85% for detection of patients who had an AMI or UA [73]. The study found that the sensitivity and specificity of MRI was greater than an abnormal ECG (80% and 61%, respectively), strict ECG criteria for ischemia (16% and 95%, respectively), peak troponin-I (40% and 97%, respectively), and TIMI risk score >3 (48% and 85%, respectively) [73]. As with other modalities discussed previously, the limitation of using myocardial perfusion and WT with CMR

is an inability to differentiate acute from chronic ischemia. This limitation was recently addressed in a study where the incremental benefit of T2-weighted imaging for myocardial edema and left ventricular wall thickness analysis were added to standard CMR, which included cine wall motion, firstpass myocardial perfusion, and delayed-enhancement imaging [74]. In a cohort of 62 patients, standard CMR had 85% sensitivity, 84% specificity, 58% positive predictive value, and 95% negative predictive value, with overall diagnostic accuracy of 84% for detection of an ACS [74]. The addition of T2-weighted imaging and left ventricular wall thickness to standard CMR increased the positive predictive value to 85% and the overall accuracy to 93%, due to the ability to differentiate new ACS from prior MI and from the detection of UA [74]. The CMR signatures for UA included the presence of signal hyperintensity on T2-weighted images from myocardial edema, without delayed hyperenhancement or necrosis. Only 2 patients with UA were missed [74]. On the other hand, patients with NSTEMI had both T2-weighted hyperintensity as well as delayed hyperenhancement, while those with remote MI demonstrated wall thinning with no myocardial edema, and those with noncardiac CP had none of these abnormalities [74]. In future, phosphorus 31 spectra using nuclear magnetic resonance (31P-NMR) spectroscopy can potentially be used to detect one of the earliest metabolic derangements due to myocardial ischemia. Metabolic derangements develop early in the ischemic cascade, and maintenance of cellular levels of high-energy phosphates is needed to preserve myocardial function. With severe myocardial ischemia, there is a rapid loss of phosphocreatine and a decrease in the ratio of phosphocreatine to ATP [75]. Using CMR, myocardial energy metabolism can be assessed with 31P-NMR spectroscopy. The use of the phosphocreatine-to-ATP ratio to detect ischemia using 31P-NMR spectroscopy was evaluated in women admitted to hospital with CP who were found to have no significant CAD on angiography [76]. The change in Â�phosphocreatine-to-ATP ratio in this group was compared to normal controls, and to patients with known severe stenosis (.70%) of the left anterior descending coronary artery. Isometric handgrip exercise at 30% of maximal grip strength was used as the stressor. In the reference group, the phosphocreatine-to-ATP ratio decreased by 2.6%  10% during stress. The decrease was significantly greater in patients with CAD, where the phosphocreatine-to-ATP ratio dropped by 20%  11%. In patients with CP but normal coronary Â�arteries, 7 of the 35 women had a significant decrease in phosphocreatine-to-ATP ratio of 29%  5.1%, presumably due to diffuse CAD with no focal luminal stenosis or microvascular disease. In the WISE study, the detection of ischemia using the phosphocreatine-to-ATP ratio has been found to predict outcome in women with CP despite the absence of epicardial CAD. Patients with an abnormal ratio had Â�significantly higher rates of hospitalization for angina, catheterization, and treatment costs [77].

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Despite its strengths, a number of obstacles may prevent CMR from becoming as widely accepted a tool as other modalities, such as the inability to image patients with claustrophobia, highly complex and lengthy studies that may be tolerated poorly by acutely ill and symptomatic patients, and contraindications in patients with implanted devices. Some logistical challenges also exist, such as the limited availability of the technology to all hospitals or the limited number of systems in a particular hospital; at least in 1 study, about 5% of eligible patients were excluded because the system was being used for other urgent cases [74]. Computed Tomography The use of CCTA for the evaluation of patients with CP and nondiagnostic ECGs has been increasing as newer technology improves the diagnostic quality of the images. The use of 64-slice MDCT scanners has shown excellent accuracy for diagnosing CAD. Newer dual-source 64-slice MDCT and 256-slice detectors may further improve temporal resolution and volume coverage, respectively [78]. Cardiac MDCT now offers isotropic resolution in the range of 400 μm. These advances allow MDCT to evaluate coronary anatomy, ventricular function, and potentially myocardial perfusion, making it an attractive option for the evaluation of patients with suspected ACS. CT also has the added advantage of having a high sensitivity for detecting other serious causes of CP such as aortic dissection and pulmonary embolism. The ability to detect and quantify the severity of a coronary stenosis gives MDCT an added benefit over the other imaging modalities discussed so far. A recent metaanalysis showed that MDCT had an 85% sensitivity and a 95% specificity for detecting a stenosis .50% in severity [79]. It is important to point out, however, that a significant number of coronary segments were excluded from analysis in many of these studies because of motion artifact or size ,2 mm. Other limitations in MDCT coronary angiography include patients with tachycardia despite the use of beta-blockade and poor visualization of segments with previous stent placement.

67

The use of MDCT in the evaluation of acute CP patients in the ED has been evaluated in only small singlecenter studies at this time. Because little data demonstrating CCTA findings in patients with and without ACS are available, there is the potential for inappropriate use of MDCT from additional testing rather than preventing admissions or cost [80]. The North American Society for Cardiac Imaging and the European Society for Cardiac Radiology therefore convened an expert panel to review the literature, identify areas that require more research, and provide interim summary recommendations in the preparation for development of comprehensive guidelines [80]. As discussed above, most patients with CP are admitted to hospital or undergo prolonged observation prior to discharge, and most will not turn out to have an ACS. The powerful negative predictive value of MDCT makes it an attractive option for exclusion of significant CAD in low-risk patients, who can potentially be discharged expediently from the ED. In 3 recent studies, all of which enrolled adult patients with acute CP that was suspected to be cardiac in etiology, but without initial ECG or serum biomarker evidence of ischemia, significant CAD Â�(stenosis .50%) was excluded in 60% to 71% of patients [81–83]. The negative predictive value of MDCT for ACS was found to range from 97% to 100% [81–83]. Cardiac event rates (cardiac death, AMI, and UAP) over a period of 6 to 15 months were very low in patients with minimal abnormalities on MDCT after discharge from the ED [81–83]. Figure 4.10 shows images from a 43-year-old woman who presented to the ED with atypical CP, normal ECG, and negative serum biomarkers. She was referred to cardiac MDCT from the ED. A curved multiplanar reformat of left anterior descending coronary artery (panel A), and multiplanar reformat of right coronary artery (panel B), demonstrated entirely normal coronary arteries, without evidence of coronary plaque or stenosis. The patient was therefore reassured that her CP was noncardiac in etiology, and she was discharged from the ED without any recommendations for further cardiac testing. Multivariate regression logistic analyses have shown that MDCT can provide independent incremental risk stratification for the development of an ACS over the

4 . 1 0 â•… Cardiovascular computed tomography angiography images from a patient presenting with chest pain.

F igure

6 8Multimodality Imaging in Cardiovascular Medicine

clinical evaluation. For every additional segment (total of 17 segments) with plaque, the average increase in odds of having ACS was 1.58 (95% confidence interval 1.18–1.87) [82]. Although patients presenting with acute CP who have significant CAD identified on MDCT are at much higher risk, the positive predictive value of an abnormal CCTA for the development of an ACS is much lower than its negative predictive value (47%–52%) [82,83]. Even though higher noncalcified plaque burden and eccentric remodeling have been found more frequently in patients with ACS, the ability to differentiate acute versus stable coronary lesions by CCTA is limited [84]. Therefore, patients with previously documented CAD or those at high risk probably will not be as suitable for evaluation by CCTA in the ED. Currently, many patients (up to 25%) may be ineligible for MDCT due to renal insufficiency, tachyarrhythmias, asthma, or inability to comply with breath-hold requirements. In a recent study, significant coronary stenosis could not be excluded in approximately 17% of studies due to the presence of a prior stent, severe calcification, poor signal-tonoise ratio, or tachycardia [82]. An important consideration for the use of CT is the exposure to a moderate amount of radiation. This is an increasingly important point of discussion as the implications of the vast amount of radiation we expose our patients to in today’s highly technological world of medicine is further investigated. However, with radiation dose–Â�reducing strategies, such as prospective triggering, radiation dose has been reduced considerably (~3–5 mSv), similar to that of an invasive coronary angiogram. Also, the need for radiographic contrast adds some risk of renal toxicity and hypersensitivity reactions. Similar to SPECT and CMR, there is also some potential danger in transporting a patient who is potentially unstable for an imaging study away from a closely monitored setting.

j â•… SUMMARY The evaluation of a patient presenting with acute CP is challenging, and making a rapid diagnosis of ACS while differentiating it from all other causes of CP is clinically difficult. The use of ancillary imaging including echocardiography, SPECT, CMR, and CT have all been evaluated in their ability to provide incremental diagnostic and prognostic information over simple bedside tools like history, physical examination, and ECG. All the technologies have their own strengths and weaknesses when compared to others. SPECT and echocardiography are well-established Â�technologies that can directly assess the presence of myocardial ischemia and its functional consequence on RF; newer and more expensive techniques such as MDCT and CMR can directly assess coronary anatomy and have just started to be evaluated in the acute CP setting. There

are few studies that directly compare these technologies, and more data are clearly needed before physicians can understand the subsets of patients who may benefit most from anatomic imaging versus perfusion/function imaging. Other comparisons such as relative safety, availability, logistics, and cost-effectiveness between the various technologies are also lacking. Other issues will also influence the choice of the modality to be used, such as the availability of personnel and infrastructure at each institution to accommodate imaging after normal working hours, rapid interpretation of studies, and quick communication of results to the ordering physician. Despite these and other questions that need to be answered before any one technique is used exclusively, the future of noninvasive cardiac imaging remains an exciting and ever changing field. The adaptation of any one of these techniques into their proper role in ED will take considerably more time and effort in terms of research, money, and clinical experience.

jâ•… REFERENCES â•‡ 1. American Heart Association. Heart Disease and Stroke Statistics— 2008 Update. Dallas, TX: American Heart Association; 2008. â•‡ 2. Silverstein MD, Heit JA, Mohr DN, Petterson TM, O’Fallon WM, Melton III LJ. Trends in the incidence of deep vein thrombosis and pulmonary embolism. A 25-year population-based study. Arch Intern Med. 1998;158:585–593. â•‡ 3. Tsai TT, Nienaber CA, Eagle KA. Acute aortic syndromes. Circulation. 2005;112:3802–3813. â•‡ 4. Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1999 Guidelines for the Management of Patients with Acute Myocardial Infarction). Circulation. 2004;110(5):588–636. â•‡ 5. Forest RS, Shofer FS, Sease KL, Hollander JE. Assessment of the standardized reporting guidelines ECG classification system: the presenting ECG predicts 30 day outcomes. Ann Emerg Med. 2004;44:206–212. â•‡ 6. Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for the management of patients with UA/non-ST-Â� elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines (Writing committee to Revise the 2002 Guidelines for the Management of Patients with Unstable Angina/Non-STElevation Myocardial Infarction): developed in collaboration with the American College of Physicians, Society for Academic Emergency Medicine, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol. 2007;50:e1–e157. â•‡ 7. Pope JH, Selker HP. Acute coronary syndromes in the emergency department: diagnostic characteristics, tests and challenges. Cardiol Clin. 2005;23:423–451. â•‡ 8. Lakkireddy DR, Kondur AK, Chediak EJ, Nair CK, Khan IA. Cardiac troponin I release in non-ischemic reversible myocardial injury from acute diphtheric myocarditis. Int J Cardiol. 2005;98:351–354. â•‡ 9. Jeremias A, Gibson CM. Narrative review: alternative causes for elevated cardiac troponin levels when acute coronary syndromes are excluded. Ann Intern Med. 2005;142:786–791.

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10. Roongsritong C, Warraich I, Bradley C. Common causes of troponin elevations in the absence of acute myocardial infarction: incidence and clinical significance. Chest. 2005;125:1877–1884. 11. Pope JH, Aufderheide TP, Ruthazer R, et al. Missed diagnosis of acute cardiac ischemia in the emergency department. N Engl J Med. 2000;342:1163–1170. 12. McCarthy BD, Beshansky JR, D’Agostino RB, Selker HP. Missed diagnoses of acute myocardial infarction in the emergency department: results from a multicenter study. Ann Emerg Med. 1993;22:579–582. 13. Lee TH, Rouan GW, Weisberg MC, et al. Clinical characteristics and natural history of patients with acute myocardial infarction sent home from the emergency room. Am J Cardiol. 1987;60:219–224. 14. Rouleau J, Boerboom LE, Surjadhana A, Hoffman JL. The role of autoregulation and tissue diastolic pressures in the transmural distribution of left ventricular blood flow in anesthetized dogs. Circ Res. 1979;45:804–815. 15. Gould KL, Lipscomb K. Effects on coronary stenoses on coronary flow reserve and resistance. Am J Cardiol. 1974;34:48–55. 16. Campeau L. Grading of angina pectoris [letter]. Circulation. 1976;54:522–523. 17. Cybulsky MI, Gimbrone MA Jr. Endothelial expression of a mononuclear leukocyte adhesion molecule during atherogenesis. Science. 1991;251:788–791. 18. Plutzky J. Inflammatory pathways in atherosclerosis and acute coronary syndromes. Am J Cardiol. 2001;88(suppl):10K–15K. 19. Leong-Poi, Coggins MP, Sklenar J, Jayaweera AR, Wang XQ, Kaul S. Role of collateral blood flow in the apparent between the extent of abnormal wall thickening and perfusion defect size during acute myocardial infarction and demand ischemia. J Am Coll Cardiol. 2005;45:565–572. 20. Heyndrickx GR, Baig H, Nellens P, Leusen I, Fishbein MC, Vatner SF. Depression of regional blood flow and wall thickening after brief coronary occlusions. Am J Physiol. 1978;234:H653–H659. 21. Kloner RA, Jennings RB. Consequences of brief ischemia: stunning, preconditioning, and their clinical implications: part 1. Circulation. 2001;104:2981–2989. 22. Nixon JV, Brown CN, Smitherman TC. Identification of transient and persistent segmental wall motion abnormalities in patients with unstable angina by two-dimensional echocardiography. Circulation. 1982;65:1497–1503. 23. Beller GA, Holzgrefe HH, Watson DD. Intrinsic washout rates of thallium-201 in normal and ischemic myocardium after dipyridamoleinduced vasodilation. Circulation. 1985;71:378–386. 24. Okada RD, Glover D, Gaffney T, Williams S. Myocardial kinetics of technetium-99m-hexakis-2-methoxy-2-methylpropyl-isonitrile. Circulation. 1988;77:491–498. 25. Wei K, Le E, Bin JP, Coggins M, Goodman NC, Kaul S. Mechanism of reversible 99mTc-sestamibi perfusion defects during pharmacologically induced coronary vasodilation. Am J Physiol. 2001;280:H1896–H1904. 26. Hunold P, Schlosser T, Barkhausen J. Magnetic resonance cardiac perfusion imaging—a clinical perspective. Eur Radiol. 2006;16:1779–1788. 27. Kramer CM. Integrated approach to ischemic heart disease: the one-stop shop. Cardiol Clin. 1998;16:267–276. 28. Wintersperger BJ, Nikolaou K, von Ziegler F, et al. Image quality, motion artifacts, and reconstruction timing of 64-slice coronary computed tomography angiography with 0.33-s rotation speed. Invest Radiol. 2006;41:436–442. 29. Stillman AE, Oudkerk M, Ackerman M, et al. Use of multidetector computed tomography for the assessment of acute chest pain: a consensus statement of the North American Society of Cardiac Imaging and the European Society of Cardiac Radiology. Int J Cardiovasc Imaging. 2007;23:415–427. 30. Wei K, Jayaweera AR, Firoozan S, Linka A, Skyba DM, Kaul S. The basis for stenosis detection using venous administration of microbubbles during myocardial contrast echo-cardiography: bolus or continuous infusion? J Am Coll Cardiol. 1998;32:252–260.

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31. Wei K, Le E, Bin JP, Coggins M, Goodman NC, Kaul S. Mechanism of reversible 99mTc-sestamibi perfusion defects during pharmacologically induced coronary vasodilation. Am J Physiol. 2001;280:H1896–H1904. 32. Heyndrickx GR, Baig H, Nellens P, Leusen I, Fishbein MC, Vatner SF. Depression of regional blood flow and wall thickening after brief coronary occlusions. Am J Physiol. 1978;234:H653–H659. 33. Kloner RA, Jennings RB. Consequences of brief ischemia: stunning, preconditioning, and their clinical implications: part 1. Circulation. 2001;104:2981–2989. 34. Nixon JV, Brown CN, Smitherman TC. Identification of transient and persistent segmental wall motion abnormalities in patients with unstable angina by two-dimensional echocardiography. Circulation. 1982;65:1497–1503. 35. Ito H, Tomooka T, Sakai N, Higashino Y, Fujii K, Katoh O, et al. Time course of functional improvement in stunned myocardium in risk area in patients with reperfused anterior infarction. Circulation. 1993;87:355–362. 36. Kaul S, Senior R, Firschke C, Wang XQ, Lindner J, Villanueva FS, et al. Incremental value of cardiac imaging in patients presenting to the emergency department with chest pain and without ST-segment elevation: a multicenter study. Am Heart J. 2004;148: 129–136. 37. Korosoglou G, Labadze N, Hansen A, et al. Usefulness of real-time myocardial perfusion imaging in the evaluation of patients with first time chest pain. Am J Cardiol. 2004;94:1225–1231. 38. Kang DH, Kang SJ, Song JM, Choi KJ, Hong MK, Song JK, et al. Efficacy of myocardial contrast echocardiography in the diagnosis and risk stratification of acute coronary syndrome. Am J Cardiol. 2005;96:1498–1502. 39. Rinkevich D, Kaul S, Wang XQ, Tong KL, Belcik T, Kalvaitis S, et al. Regional left ventricular perfusion and function in patients presenting to the emergency department with chest pain and no ST-segment elevation. Eur Heart J. 2005;26:1606–1611. 40. Antman E, Cohen M, Bernink PJL, et al. The TIMI risk score for unstable angina/non-ST elevation MI: a method for prognostication and therapeutic decision making. JAMA. 2000; 284: 835–842. 41. Tong KL, Kaul S, Wang XQ, Rinkevich D, Kalvaitis S, Belcik T, et al. Myocardial contrast echocardiography versus thrombolysis in myocardial infarction score in patients presenting to the emergency department with chest pain and a nondiagnostic electrocardiogram. J Am Coll Cardiol. 2005;46:920–927. 42. Kalvaitis S, Kaul S, Tong KL, Rinkevich D, Belcik T, Wei K. Effect of time delay on the diagnostic use of contrast echocardiography in patients presenting to the emergency department with chest pain and no S-T segment elevation. J Am Soc Echocardiogr. 2006;19:1488–1493. 43. Wyrick JJ, Kalvaitis S, McConnell J, Rinkevich D, Kaul S, Wei K. Cost efficiency of myocardial contrast echocardiography in patients presenting to the emergency department with chest pain of suspected cardiac origin and a non-diagnostic electrocardiogram . Am J Cardiol. 2008;102:649–652. 44. Christiansen JP, Leong-Poi H, Klibanov AL, Kaul S, Lindner JR. Noninvasive imaging of myocardial reperfusion injury using leukocyte-targeted contrast echocardiography. Circulation. 2002;105:1764–1767. 45. Weller GER, et al. Ultrasound imaging of acute cardiac transplant rejection with microbubbles targeted to intercellular adhesion molecule-1. Circulation. 2003;108:218–224. 46. Lindner JR, et al. Ultrasound assessment of inflammation and renal tissue injury with microbubbles targeted to P-selectin. Circulation. 2001;104:210–212. 47. Lang RM, Mor-Avi V, Sugeng L, Nieman PS, Sahn DJ. Threedimensional echocardiography: the benefits of the additional dimension. J Am Coll Cardiol. 2006;48:2053–2069. 48. Hung J, Lang R, Flachskampf F, et al. 3D Echocardiography: a review of the current status and future directions. J Am Soc Echocardiogr. 2007;20:213–233.

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49. Kusnetzky LL, Khalid A, Khumri TM, Moe TG, Jones PG, Main ML. Acute mortality in hospitalized patients undergoing echocardiography with and without an ultrasound contrast agent: results in 18,671 consecutive studies. J Am Coll Cardiol. 2008;51:1704–1706. 50. Wei K, Mulvagh SL, Carson L, et al. The safety of definity and optison for ultrasound image enhancement: a retrospective analysis of 78,383 administered contrast doses. J Am Soc Echocardiogr. 2008;11:1202–1206. 51. Varetto T, Cantalupi D, Altieri A, et al. Emergency room technetium-99m sestamibi imaging to rule out acute myocardial ischemic events in patients with nondiagnostic electrocardiograms. J Am Coll Cardiol. 1993;22:1804–1808. 52. Hilton TC, Thompson RC, Williams HJ, et al. Technetium-99m sestamibi myocardial perfusion imaging in the emergency room evaluation of chest pain. J Am Coll Cardiol. 1994;23:1016–1022. 53. Tatum JL, Jesse RL, Kontos MC, et al. Comprehensive strategy for the evaluation and triage of the chest pain patient. Ann Emerg Med. 1997;29:116–123. 54. Kontos MC, Jesse RL, Schmidt KL, et al. Value of acute rest sestamibi perfusion imaging for evaluation of patients admitted to the emergency department with chest pain. J Am Coll Cardiol. 1997;30:976–982. 55. Heller GV, Stowers SA, Hendel RC, et al. Clinical value of acute rest technetium-99m tetrofosmin tomographic myocardial perfusion imaging in patients with acute chest pain and nondiagnostic electrocardiograms. J Am Coll Cardiol. 1998;31:1011–1017. 56. Kontos MC, Jesse RL, Anderson FP, et al. Comparison of myocardial perfusion imaging and cardiac troponin I in patients admitted to the emergency department with chest pain. Circulation. 1999;99:2073–2078. 57. Udelson JE, Beshansky JR, Ballin DS, et al. Myocardial perfusion imaging for evaluation and triage of patients with suspected acute cardiac ischemia: a randomized controlled trial. JAMA. 2002;288:2693–2700. 58. O’Connor MK, Hammell T, Gibbons RJ. In vitro validation of a simple tomographic technique for estimation of percentage myocardium at risk using methoxyisobutyl isonitrile technetium 99m (sestamibi). Eur J Nucl Med. 1990;17:69–76. 59. Mannting F, Morgan-Mannting MG. Gated SPECT with technetium99m-sestamibi for assessment of myocardial perfusion abnormalities. J Nucl Med. 1993;34:601–608. 60. Kaul S, Senior R, Harrel FE, et al. Incremental value of cardiac imaging in patients presenting to the emergency department with chest pain and without ST-segment elevation: A multicenter study. Am Heart J. 2004;148:129–136. 61. Heller GV, Udelson JE, Ziffer J, et al. Assessing suspected acute cardiac ischemia in the emergency department: logistics, testing modalities, implications for perfusion imaging. J Nucl Cardiol. 2001;8:274–285. 62. Kontos MC, Tatum JL. Imaging in the evaluation of the patient with suspected acute coronary syndrome. Semin Nucl Med. 2003;4:246–258. 63. Dilsizian V, Bateman TM, Bergmann SR, et al. Metabolic imaging with beta-methyl-p-[(123)I]-iodophenyl-pentadecanoic acid identifies ischemic memory after demand ischemia. Circulation. 2005;112:2169–2174. 64. Goodman MM, Kirsch G, Knapp FF Jr. Synthesis and evaluation of radioiodinated terminal p-iodophenyl substituted a- and b-methyl branched fatty acids. J Med Chem. 1984;27:390–397. 65. Cave AC, Ingwall JS, Friedrich J, et al. ATP synthesis during low-flow ischemia: influence of increased glycolytic substrate. Circulation. 2000;101:2090–2096. 66. Wagner S, Auffermann W, Buser P, Semelka RC, Higgins CB. Functional description of the left ventricle in patients with volume overload, pressure overload, and myocardial disease using cine magnetic resonance imaging. Am J Cardiac Imag. 1991;5:87–97. 67. Lotz J, Meier C, Leppert A, Galanski M. Cardiovascular flow measurement with phase-contrast MR imaging: basic facts and implementation. Radiographics. 2002;22:651–671.

68. Kim RJ, Chen EL, Lima JA, Judd RM. Myocardial Gd-DTPA kinetics determine MRI contrast enhancement and reflect the extent and severity of myocardial injury after acute reperfused infarction. Circulation. 1996;94:3318–3326. 69. Kim RJ, Fieno DS, Parrish TB, et al. Relationship of MRI delayed contrast enhancement to irreversible injury, infarct age, and contractile function. Circulation. 1999;100:1992–2002. 70. Setser RM, Bexell DG, O’Donnell TP, et al. Quantitative assessment of myocardial scar in delayed enhancement magnetic resonance imaging. J Magn Reson Imag. 2003;18:434–441. 71. Aletras AH, Tilak GS, Natanzon A, et al. Retrospective determination of the area at risk for reperfused acute myocardial infarction with T2-weighted CMR imaging: histopathological and displacement encoding with stimulated echoes (DENSE) functional validations. Circulation. 2006;113:1865–1870. 72. Kaandorp TAM, Lamb HF, Bax JJ, van der Wall EE, de Roos A. Magnetic resonance imaging of coronary arteries, the ischemic cascade, and myocardial infarction. Am Heart J. 2005;149:200–208. 73. Kwong RY, Schussheim AE, Rekhraj S, et al. Detecting acute coronary syndrome in the emergency department with cardiac magnetic resonance imaging. Circulation. 2003;107:531–537. 74. Cury RC, Shash KS, Nagurney JT, et al. Cardiac magnetic resonance with T2-weighted imaging improves detection of patients with acute coronary syndrome in the emergency department. Circulation. 2008;118:837–844. 75. Kawai Y, Tsukamoto E, Nozaki Y, Morita K, Sakurai M, Tamaki N. Significance of reduced uptake of iodinated fatty acid analogue for the evaluation of patients with acute chest pain. J Am Coll Cardiol. 2001:38;1888–1894. 76. Buchthal SD, den Hollander JA, Merz CN, et al. Abnormal myocardial phosphorus-31 nuclear magnetic resonance spectroscopy in women with chest pain but normal coronary angiograms. N Engl J Med. 2000;342:829–835. 77. Johnson BD, Shaw LJ, Buchthal SD, et al. Prognosis in women with myocardial ischemia in the absence of obstructive coronary disease: results from the National Institutes of Health-National Heart, Lung, and Blood Institute-Sponsored Women’s Ischemia Syndrome Evaluation (WISE). Circulation. 2004:109:2993–2999. 78. Wintersperger BJ, Nikolaou K, von Ziegler F, et al. Image quality, motion artifacts, and reconstruction timing of 64-slice coronary computed tomography angiography with 0.33-s rotation speed. Invest Radiol. 2006;41:436–442. 79. Schuijf JD, Bax JJ, Wijns W, et al. Meta-analysis of comparative diagnostic performance of magnetic resonance imaging and multislice computed tomography for noninvasive coronary angiography. Am Heart J. 2006;15:404–411. 80. Stillman AE, Oudkerk M, Ackerman M, et al. Use of multidetector computed tomography for the assessment of acute chest pain: a consensus statement of the North American Society of Cardiac Imaging and the European Society of Cardiac Radiology. Int J Cardiovasc Imaging. 2007;23:415–427. 81. Rubinshtein R, Halon DA, Gaspar T, et al. Usefulness of 64-slice cardiac computed tomographic angiography for diagnosing acute coronary syndromes and predicting clinical outcome in emergency department patients with chest pain of uncertain origin. Circulation. 2007;115(13):1762–1768. 82. Hoffmann U, Nagurney JT, Moselewski F, et al. Coronary multidetector computed tomography in the assessment of patients with acute chest pain. Circulation. 2006;114(21):2251–2260. 83. Goldstein JA, Gallagher MJ, O’Neill WW, Ross MA, O’Neil BJ, Raff GL. A randomized controlled trial of multi-slice coronary computed tomography for evaluation of acute chest pain. J Am Coll Cardiol. 2007;49(8):863–871. 84. Motoyama S, Kondo T, Sarai M, et al. Multislice computed tomographic characteristics of coronary lesions in acute coronary syndromes. J Am Coll Cardiol. 2007;50:319–326.

5

Post-MI Risk Stratification

M ARK R. VESELY JAmES A . A RRI GHI GAGANDEEP S . GUR m HARISHA KO mmANA VASKEN D ILSIZIAN jâ•… INTRODUCTION Acute myocardial infarction (MI) is highly prevalent in the United States, occurring every 34 seconds [1]. This results in an estimated 610 000 first-time and 325 000 recurrent MIs annually, many of which are fatal events. A wide variability persists in post-MI mortality based on age, race, and gender. For example, 15% of white men between 40 and 69 years of age and 62% of black women 70 years or older will die within 5 years following a first MI [1]. While annual MI-related death rates declined 34% from 1995 to 2005 [2], there remains an average 15 years of life lost following an MI [3]. Likewise, patients who have survived an MI are at increased risk of future cardiac events such as a subsequent MI and development of heart failure or life-threatening arrhythmias. Predicting who will experience further clinical difficulties following an MI is thus an important endeavor. The characterization of risk for future cardiac events enables management choices to be made at an individualized level, thus matching the utilization of diagnostic and therapeutic modalities to a patient’s risk of future cardiac events or death. The risk for adverse outcome following acute MI is affected by a number of variables. These include historical and demographic factors, markers of clinical stability, and various biomarkers that assess infarct size or heart failure [4–18]. Factors related to the residual structure and function of the post-MI heart play an important role in a patient’s vulnerability for future cardiac events or death. Specifically, the state of LV function, presence of electrical instability, and the amount of ischemic but viable myocardium perfused by stenotic coronary arteries are important prognostic factors [19,20]. The importance of risk assessment using such physiologic measures is highlighted by

experimental and clinical evidence of the great variability in infarct size for a given coronary occlusion [21–23]. The physiologic assessment of patients after MI can be achieved by numerous noninvasive imaging Â�modalities, including transthoracic echocardiography (TTE), Â�cardiac computed tomography, cardiac magnetic resonance imaging (CMR), and radionuclide cardiac Â�imaging with Â�single photon emission computed tomography (SPECT), or Â�positron emission tomography (PET). The selection of which test to perform is based on the specific clinical Â�question, the relative advantages of one test over another in the particular clinical situation, and the availability of local expertise and technology. The goal of this Â�chapter is to review the various imaging modalities utilized in Â�post-MI risk assessment in order to facilitate their Â�appropriate use. The major utility of cardiac imaging in the post-MI population is in assessing several of the most important factors that affect long-term risk. These include (1) left ventricular (LV) function, which may lead to heart failure; (2) the extent of residual myocardial ischemia/viability, which may lead to recurrent MIs; and (3) the likelihood of sudden cardiac death (SCD) based on certain functional parameters.

jâ•…I NI TIAL ACUTE MI MANAGEMENT CONTRIBUTES TO POST-MI RISK STRATIFICATION There are significant differences in the management of acute MI patients based on initial presentation. Acute MI patients with ECG evidence of ST segment elevation (STEMI) are usually treated with prompt revascularization by percutaneous coronary intervention (PCI) during cardiac catheterization or with fibrinolytic therapy [24]. In contrast, patients suffering a non-ST segment elevation MI (NSTEMI) can be managed with either an early invasive strategy (ie, cardiac catheterization) or conservatively with medical therapies [25]. Likewise, patients presenting late in the course of their MI may be managed with invasive or noninvasive strategies, depending on their clinical presentation. There is considerable overlap of the approaches to assessment of risk and management for these clinically different patient populations. 71

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In STEMI patients initially treated with PCI, early risk stratification for 30-day and 1-year mortality can be completed with multimodality scoring systems such as the Zwolle primary PCI index [26] and CADILLAC risk score [27]. These systems are derived by assessment of both clinical variables and factors obtained by imaging, including left ventricular ejection fraction (LVEF), number of diseased coronary vessels, and post-PCI TIMI flow grade in the infarct-related vessel. STEMI patients treated with fibrinolytic agents are risk stratified using risk scores such as the TIMI risk score, TIMI risk index, and GRACE risk model, which are based on clinical information at initial presentation [28–30]. Many such patients will subsequently undergo cardiac catheterization as part of the initial management and risk stratification process. Patients with STEMI who do not undergo cardiac catheterization and/or reperfusion therapy, however, are most likely to benefit from noninvasive risk stratification, which usually includes assessment of LV function and ischemic burden. Risk stratification in patients with acute NSTEMI begins at the initial presentation, to identify those at immediate high risk. Unstable patients secondary to cardiogenic shock, overt heart failure, ventricular arrhythmias, or mechanical complications should undergo coronary angiography as soon as possible with reperfusion therapy as indicated thereafter. Non–high-risk patients are further assessed to identify patients likely to benefit by an early invasive treatment plan, including cardiac catheterization within 4 to 48 hours. Except for low-risk patients (TIMI

The assessment of LV size and function is an important component of risk stratification after any type of MI. This can be accomplished with invasive or noninvasive imaging techniques. In 1960, biplane left ventriculography was first utilized for calculation of LV volumes during cardiac catheterization [33]. Twenty years later, functional and volumetric data derived from biplane left ventriculography was shown to be useful in predicting post-MI outcome. Among patients with acute MI undergoing cardiac catheterization prior to discharge from the index hospitalization, those with a post-MI LVEF of ,40% had increased risk for death after discharge compared to those with relatively preserved LVEF [34]. Subsequent studies have shown that beyond LVEF, LV end-systolic volume (ESV) independently predicted post-MI mortality (Figure 5.1) [35]. In the

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risk score 0–2), such prompt angiography and as-needed reperfusion are recommended in NSTEMI patients diagnosed by elevation of cardiac enzymes [25,31,32]. NSTEMI risk stratification in patients at the lower end of the risk spectrum is largely achieved with noninvasive cardiac imaging. Such patients who have not received complete revascularization within their early MI management benefit from prehospital discharge determination of residual myocardial ischemia [25].

ESV<130ml (n=53) 16 ESV130ml (n=53) 10

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F igure 5 . 1 â•…Survival curves demonstrating the relationship between future cardiac death and (A-top) left ventricular ejection fraction (LVEF)

and (A-bottom) LVESV (P , .001 independently), when assessed with transthoracic echocardiography 1 to 2 months following acute myocardial infarction. (B) When used to subdivide patients already grouped by LVEF, LVESV adds additional predictive value in patients with LVEF ,50%. Of note, patients with LVEF 40% to 49% and LVESV below the median (95 mL) had equivalent mortality to patients with LVEF .49% (B-middle). ESV, end-systolic volume; EF, ejection fraction. Adapted from Ref. 35.

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era of thrombolysis and coronary artery reperfusion, despite improvements in post-MI morbidity and mortality [36], LV indices of function and volumes have continued to provide significant prognostic information. In recent years, coronary artery reperfusion with PCI is performed more commonly than thrombolysis. Although left ventriculography can be performed immediately post-PCI, both LVEF and ESV are sensitive to myocardial stunning and loading conditions, which are in flux in the acute MI and post-PCI setting [37]. Accordingly, current clinical practice has moved away from acquiring left ventriculography post-PCI in order to allow stabilization of contractile dysfunction and loading conditions as well as to limit excess exposure to iodinated contrast. Instead, noninvasive imaging techniques are typically performed to assess LVEF and volumes in postMI patients, when clinically appropriate. As myocardial stunning resolves over ensuing days or weeks following MI and coronary artery reperfusion, LVEF and volumes may improve [38–41]. Patients exhibiting improvement in LVEF within 6 months of reperfusion therapy were shown to have decreased Â�mortality over the next 3 years when compared to those with worsening or no change in LVEF postreperfusion therapy [38] (Figure 5.2). Regarding the specific technique applied to compute LVEF or volumes, a recent study comparing TTE and CMR highlighted significant differences in measures of LVEF, volumes, and wall motion abnormalities between the 2 techniques [42]. Thus, in order to maximize the clinical utility of these measures and to reliably assess therapeutic responses and patient outcome, serial assessments of LV indices should be made with the same technique. Transthoracic Echocardiography

Probability of Survival % 85 90 95

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Echocardiography is the most commonly performed noninvasive imaging technique for the assessment of LVEF,

ESV, and wall motion abnormalities. While quantitative echocardiographic measures are available, most clinical echocardiographic studies are interpreted qualitatively. Even with quantitative methods, the accuracy of 2-dimensional (2D) echocardiographic measures can be limited due to geometric assumptions regarding the shape of the LV Â�cavity. Error in chamber volume calculations can be further amplified when these assumptions are made in the presence of regional hypokinesis or akinesis typically seen in the postMI setting [43]. Thus, echocardiographic interpretations are highly dependent on the experience of the reader, leading to significant interstudy and interobserver Â�variability in calculation of LVEF [44,45]. For assessing overall LV function, however, echocardiography has proven to be reasonably accurate and is a class I recommendation for postacute MI assessment of LV function in current guidelines [24,25]. The technique is noninvasive, free of ionizing radiation, and provides additional anatomic information on valve structure, diastolic function, and right ventricular function—all easily obtained as a portable study and within a reasonable time frame. Beyond LVEF and volumes, regional wall motion abnormalities, LV diastolic dysfunction, and ischemic mitral regurgitation have also been associated with cardiac death and/or major cardiovascular events postacute MI. In the post-MI setting, as compensatory regional hyperkinesis of remote myocardial walls may preserve overall LVEF, characterization of regional hypokinesis beyond a simple computation of LVEF can be quite helpful. A wall motion score index is calculated by scoring each of the 17 standard LV segments, and then dividing the summed score by the number of total segments assessed. Thus, patients with severe wall motion abnormalities are assigned with a higher wall motion index score. Among 767 patients with acute MI who were followed up for a median of 19 months post-MI, a high wall motion index score was shown to be a strong predictor of death (P , .00001), independent of

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F igure 5 . 2 â•… Change in left ventricular (LV) ejection fraction in the 6 months following acute MI (worsened, intermediate, or improved function) is predictive of future cardiac mortality. Time 0 indicates the 6-month time point following the acute myocardial infarction. Adapted from Ref. 38.

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LVEF [46]. Likewise, LV diastolic dysfunction, assessed by the restrictive transmitral LV filling pattern on TTE, was shown to be an independent parameter for predicting post-MI mortality. A meta-analysis of 12 prospective studies including 3396 patients with first acute MI (MeRGE study) confirmed the association of the restrictive transmitral LV filling pattern with higher cardiac death and allcause mortality [47]. Ischemic mitral regurgitation following MI has also been shown to be an independent predictor of mortality. Among 194 postacute MI patients, TTE-defined ischemic mitral regurgitation was associated with increased risk of mortality. The more extensive the severity of mitral regurgitation, the higher the mortality [48]. An incremental risk stratification scheme that includes regional wall motion abnormalities, LV diastolic dysfunction, and ischemic mitral regurgitation to LVEF and ESV has not been derived. TEE could be considered as an alternative if TTE is not diagnostic. TEE can better identify aortic aneurysm, aortic dissection, atheromatous plaques, and intracardiac thrombi. However, it is not typically used in the acute MI setting unless for the specific indications mentioned. Radionuclide Imaging

Gated Equilibrium Blood Pool Gated equilibrium blood pool (MUGA) imaging provides a highly accurate quantitative assessment of global LVEF and RVEF. Quantification of ejection fraction (EF) by either first-pass or gated equilibrium radionuclide angiography is count based and independent of ventricular geometry. Qualitative assessment of regional LV function, right ventricular function, and sizes of major vascular structures also is performed on a typical gated blood pool study. Assessment of LVEF remains a mainstay of prognostic assessment after MI regardless of whether reperfusion therapy was performed. Prior to the reperfusion era, predischarge radionuclide assessment of resting LVEF was found to predict post-MI mortality. In the Multicenter Postinfarction Research Group study [49], data in 866 patients showed a progressive increase in cardiac mortality during 1 year as the LVEF decreased below 40% [50] (Figure 5.3). In a subsequent publication where the role of reperfusion therapy was assessed in patients with acute MI [51], LVEF continued to be an important predictor of subsequent patient outcome. Studies also have demonstrated the prognostic significance of LVEF in patients who received thrombolytic therapy for AMI [52,53]. Patients who received thrombolytic therapy but had LVEF ,30% at discharge exhibited mortality rates above 50% at 5 years [53]. In contrast, patients with relatively preserved LVEF at discharge (EF .40%) experienced an annual mortality rate of nearly 2% per year.

Multimodality Imaging in Cardiovascular Medicine

F igure 5 . 3 â•…One-year mortality as a function of left ventricular Â�ejection fraction in the multicenter postinfarction trial (MPIT) and the thrombolysis in myocardial infarction II (TIMI) trial. Adapted from Ref. 50.

In addition to LVEF, measurement of LV size also carries prognostic significance after MI. In particular, LV ESV and overall infarct size are important predictors of cardiac events and death [35,54–59]. Thus, radionuclide imaging has a class I recommendation for assessment of ventricular dimensions and function as well as infarct size, in both the post-STEMI and non-STEMI populations [24,60]. While exercise-gated equilibrium blood pool imaging has also been employed for risk stratification postacute MI, this technique is rarely performed in this setting [61,62].

Myocardial Perfusion Imaging Myocardial perfusion imaging (MPI) with SPECT or PET is the most widely used nuclear cardiology technique and fulfills a number of roles. MPI can be used to assess infarct size, myocardial viability, stress-induced ischemic burden, LVEF, regional wall motion, and LV size. Protocols may be optimized for the specific clinical situation, and thus this technique has proven to be extremely versatile and valuable in the post-MI setting. The importance of functional assessment of post-MI patients has been demonstrated in many studies. When perfusion imaging variables (using thallium) were assessed following acute MI [63], the combination of reversible defects and increased lung-to-heart ratio had a significantly greater sensitivity for predicting future cardiac events than submaximal exercise ECG testing or coronary angiography [63]. Identification of a low-risk subgroup was performed more effectively with MPI [63]. Even with pharmacologic stress, the presence of reversible defects on MPI is a powerful predictor of cardiac death post-MI [56]. Of note, pharmacologic stress MPI, using vasodilator stress, can be performed safely as early as 2 to 3 days after uncomplicated MI.

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Assessment of Myocardial Salvage.â•… A potential role for MPI, albeit infrequently utilized, is assessing the degree of myocardial salvage after reperfusion therapy for MI. Studies in patients receiving intracoronary thrombolytic therapy demonstrated that improvement in thallium uptake during the postinfarction period is associated with coronary reperfusion [64,65], whether spontaneous or as a result of thrombolytic treatment. Such improvements may occur over several months after treatment [64], suggesting a gradual improvement in cellular uptake mechanisms with time. Evidence of reperfusion was correlated with improved LV performance on hospital discharge, indicating myocardial salvage [65]. Tc 99m–based perfusion tracers may be particularly useful for the assessment of myocardial salvage, given their lack of significant redistribution, which allows greater temporal separation between the time of isotope injection and that of imaging. Specifically, the injection of the tracer during the acute phase of MI before reperfusion therapy may represent a true estimate of risk area and can be employed to assess the degree of myocardial salvage after thrombolytic therapy or direct angioplasty. After injection, imaging can be delayed for several hours during which therapy is administered and the patient is stabilized. The initial images, which can be acquired several hours after administration of the radiotracer, reflect the perfusion pattern at the time of tracer injection and vessel occlusion (myocardial risk area assessment). Approximately 24 hours after reperfusion therapy, a second injection of tracer can be performed at rest. The second set of images reflects the extent of myocardial salvage in the infarct-related artery. Assessment of myocardial risk area and myocardial salvage has been shown in experimental animal models. In an animal model of acute coronary artery occlusion and reperfusion, in which the relationship between sestamibi uptake and blood flow was assessed, sestamibi uptake correlated closely with blood flow assessed by microspheres, and the risk area on autoradiography correlated with the post-mortem angiographic risk area [66]. When the radiotracer was injected after reperfusion, however, its uptake tracked infarct size but no longer tracked myocardial blood flow, indicating that its uptake reflected myocardial viability. Such good correlation between scintigraphic infarct size (assessed by ex vivo tomographic sestamibi images) and pathologic infarct size (assessed histochemically) has been demonstrated by other investigators [67]. The assessment of myocardial salvage with MPI is rarely performed at present, since most patients with acute STEMI are treated with PCI or early coronary angiography. As such, its role in assessment of post-MI patients is limited. Assessment of Infarct Size.â•… Clinical studies indicate that late (predischarge) sestamibi images may be used to estimate final infarct size, and that this estimate correlates well to other measures of final infarct size such as global

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ejection fraction and peak creatine phosphokinase release. Christian and colleagues demonstrated close correlations between final defect size and several functional parameters including end-diastolic volume index, end-systolic volume index, and EF at 1-year follow-up [68]. In a subsequent study, in which the feasibility of serial tomographic sestamibi imaging was assessed to measure myocardial salvage, a significant decrease in sestamibi defect size was observed, from acute to discharge imaging, among patients who were treated with thrombolytic therapy compared to those who were not [69]. These findings were confirmed by other investigators [70,71]. Santoro and colleagues reported a good correlation between final defect size and enzymatic infarct size, as well as between improvement in perfusion defect and decrease in regional LV dysfunction from acute to predischarge imaging [71]. In patients undergoing direct angioplasty for acute MI [70], although a significant decrease in sestamibi defect size was observed between acute and late imaging, this effect was highly variable. Because the area of myocardial risk varies widely even for similar anatomical location of coronary artery occlusion, it underscores the role for assessment of myocardial perfusion and/or function in such patients. Assessment of infarct size with MPI, therefore, may be a useful prognostic tool in selected patients after acute MI. Experimentally, this technique also can be used for assessing the efficacy of new pharmaceutical agents or revascularization techniques.

Cardiac Magnetic Resonance Imaging Assessment of LV Function.â•… CMR is a potentially versatile technique for assessing cardiac structure and function. Initial applications were focused on defining overall heart size and function. Images can be obtained in any plane and without ionizing radiation exposure. For calculation of LVEF, CMR has high reproducibility in normal, dilated, and hypertrophied hearts [44] and can be paired with dobutamine stress for assessing inducible ischemia post-MI [72]. As such, CMR has become the gold standard method for assessing LV dimensions, volume, and function [73–75]. Assessment of Infarct Size.â•… Delayed-enhancement (DE) CMR is highly accurate in defining the extent of scar in patients with chronic CAD. Gadolinium, a commonly used contrast agent in MRI, concentrates in the interstitial space of infarcted myocardium. This technique, therefore, can detect myocardial scar with high accuracy, in part due to its high spatial resolution. CMR may be particularly useful in detecting small, sometimes clinically silent, old MIs. Both in experimental studies in animals and in human subjects, CMR has shown to provide improved detection of nontransmural infarctions when compared to SPECT imaging [76] (Figure 5.4). The assessment of infarct size by CMR has been performed in patients with chronic CAD and MI at least 3 months old [77].

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F igure 5 . 4 â•… The panel illustrates single photon emission computed tomography (SPECT) and cardiac magnetic resonance imaging (CMR) charac-

terization of a nearly transmural inferior infarct in a dog, as confirmed with histology. Adapted from Ref. 76.

CMR Studies in Acute Infarction Several studies have indicated that CMR may be useful to assess infarct size early after infarction. Kim and colleagues initially studied this technique in an animal model of infarction and reported that hyperenhancement correlated well with histopathologic extent of scar in both recent and chronic MI [80]. These findings were confirmed in other experimental studies, where hyperenhancement did not occur without irreversible injury to the myocardium [81,82]. The technique of DE-CMR has been subsequently studied in humans and appears to be highly accurate in delineating the extent of myocardial scar after infarction. Several studies have investigated DE-CMR within 10 days of acute infarction. Gerber et al performed DE-CMR at 4 days and 7 months post-MI, and found that lack of hyperenhancement was an accurate predictor of subsequent improvement in regional ventricular function [83]. Furthermore, the degree of functional improvement correlated with the transmural extent of hyperenhancement. Early hypoenhancement was not a good predictor of functional recovery. A subsequent study by Beek and colleagues, in which DE-CMR was performed within 10 days of reperfused infarction, confirmed that the transmural extent of hyperenhancement predicts subsequent functional recovery (Figure 5.5) [84]. Assessment of microvascular dysfunction early after MI also may have prognostic importance. Among 67 patients who underwent contrast-enhanced CMR 4.5  2.5 days following a first STEMI, the subgroup of patients who suffered major cardiovascular events at 1-year follow-up exhibited lower baseline LVEF (44%  17% vs. 48%  14%; P , .001), greater infarct size (14%  10% vs. 8%  6%; P , .001), and more significant microvascular obstruction

80 70 60 % Improvement

Moreover, regional heterogeneity of contrast enhancement on CMR has been associated with significant microvascular obstruction [78], which has also been associated with increased risk for recurrent major cardiac events or death [79]. The incremental benefit of assessing infarct size in patients with chronic CAD, however, remains unclear.

50 40 30 20 10 0 0%

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F igure 5 . 5 â•… Functional outcomes of dysfunctional segments according to

baseline segmental extent of hyperenhancement (SEH) by cardiac magnetic resonance imaging. Black bars indicate any functional improvement by SEH. Gray bars indicate complete recovery (CR) of function by SEH. Adapted from Ref. 84.

(3%  5% vs. 2%  3%; P , .001) [85]. When accounting for age, gender, and diabetes mellitus, multivariate logistic regression demonstrated only microvascular obstruction to be independently correlated with outcome. Although these initial investigations in acute MI are promising, there are data which suggest that assessment of infarct size by DE-CMR early after infarction may be imprecise. In 23 patients studied within 4 days of acute MI, Kramer et al reported that functional improvement was often observed in regions with hyperenhancement on CMR, although an older pulse sequence was used for the assessment of enhancement [86]. More recently, Ingkanisorn and coworkers performed DE-CMR in 33 patients within 0 to 5 days after MI, and in 10 patients with chronic, healed infarction [87]. Although the extent of hyperenhancement on CMR correlated well with infarct size by peak Â�troponin-I in reperfused infarction, there

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F igure 5 . 7 â•…Long-axis view of cardiac computed tomography scan obtained 51 minutes after angioplasty for acute myocardial infarction. Arrows indicate subendocardial hyperenhancement of the posterior wall, consistent with predominantly viable myocardium, which was confirmed by dobutamine echocardiography. Ao; aorta, LA; left atrium, LV; left ventricle. Adapted from Ref. 91.

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F igure 5 . 6 â•… The cardiac magnetic resonance infarct size decreases

between the acute and the follow-up cardiac magnetic resonance scan based on grams of myocardium with delayed enhancement (A) or percent of myocardium that showed delayed enhancement (B). For comparison purposes, similar measurements in patients with chronic myocardial infarction do not change significantly between serial cardiac magnetic resonance scans (C and D). LV, left ventricle; NS, not significant. Adapted from Ref. 87.

was no such correlation in patients who were not reperfused. Furthermore, when infarct size was reassessed by CMR at least 2 months later, the estimate of infarct size decreased from 16%  12% to 11%  9% in patients initially studied soon after infarction (P , .003), but remained stable (11%  4% to 12%  7%, P 5 not significant) in patients with chronic healed infarction (Figure 5.6). These data suggest that while the overall accuracy of DE-CMR in the estimation of infarct size is favorable, the Â�stability of the measurement, particularly comparing early versus late post-MI, is unclear as infarct involution takes place over time. Additionally, it should be noted that DE-CMR does not currently differentiate normal myocardium from viable, Â�ischemic myocardium [88]. This Â�distinction may be important, given the PET literature that indicates the importance of identifying the Â�flow-metabolism mismatch pattern (myocardial hibernation) as a means to guide revascularization.

Cardiac Computed Tomography Cardiac CT is an emerging technique, with limited data concerning its role for assessment of MI and salvage in the setting of acute MI. Initial studies, however, indicate that evaluation

F igure 5 . 8 â•…Short-axis view of cardiac computed tomography scan obtained 51 minutes after angioplasty for acute myocardial infarction. Arrows indicate transmural hyperenhancement of the anterospetal region, consistent with nonviable myocardium, which was confirmed by dobutamine echocardiography. LA, left atrium; LV, left ventricle; RA, right atrium; RV; right ventricle. Adapted from Ref. 91.

of myocardial contrast on cardiac CT may be used to assess myocardial viability early after infarction. Mahnken and colleagues performed cardiac CT within 2 weeks of Â�reperfused MI and showed that myocardial Â�contrast enhancement during the late phase of imaging (15 minutes after contrast injection) correlated well with viability assessment using Â�contrast-enhanced MRI [89]. The potential Â�utility of cardiac CT in these patients has been confirmed by other investigators as well [90]. More recently, Habis and coworkers studied a novel approach to cardiac CT. These investigators performed CT imaging within 50 minutes after routine coronary Â�angiography, Â�without additional contrast injection [91]. Using this Â�technique, the degree of myocardial enhancement was predictive of subsequent improvements in regional ventricular function during follow-up (Figures 5.7 and 5.8). Further studies need to be performed to investigate the role of Â�cardiac CT for this indication.

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jâ•…A SSESSING MYOCARDIAL IS CHEMIA, VIABILITY, AND RISK OF SUDDEN DEATH As noted above, the long-term risk after acute MI is determined by a number of variables, including LV function and/or infarct size, extent of residual myocardial ischemia/ viability, and likelihood of SCD. A number of imaging techniques may provide information on coronary anatomy, ischemia, and viability that may have an impact on predicting risk of adverse outcome. In particular, the utilization of cardiac imaging to assess coronary anatomy, ischemic burden, and myocardial viability may be very important in identifying those patients who may benefit from advanced invasive therapies such as coronary revascularization and/ or implantable cardioverter-defibrillators. Predicting Benefit of Revascularization The decision to revascularize a patient after MI is based on a number of factors. In the acute MI setting in which a patient is likely to have undergone at least partial revascularization during PCI, the decision is most often based on coronary anatomy and/or clinical or objective evidence of ongoing ischemia. In the more chronic stages after MI, the decision may be based on these same factors, as well as LV function, evidence of ischemia on stress testing, and evidence of significant residual myocardial viability. In patients with angina, the decision to revascularize is often relatively straightforward, since a major benefit of the procedure is improvement in symptoms. On the other end of the spectrum, patients with ischemic cardiomyopathy often require objective assessment of myocardial ischemia and viability in order to guide therapy. Cardiac imaging is helpful in characterizing the coronary atherosclerotic burden and the presence and extent of myocardial ischemia and viability, and accordingly, guide revascularization and/or medical therapy. CAD Burden The presence and extent of atherosclerotic coronary artery lesions are typically determined during the initial invasive acute MI management with cardiac catheterization. Selective coronary angiography, as the gold standard technique for assessing CAD, is a class I recommendation in patients with acute ST segment elevation MI (STEMI) or in high-risk NSTEMI patients [25,92]. In some medical centers, STEMI patients receive thrombolytics and NSTEMI patients are managed conservatively, such that angiography is not part of the initial acute MI management. In these patients, noninvasive assessment by CTA is an alternative approach. While CTA has had challenges for identifying lesions in small diameter and tortuous coronary arteries and/or motion of the beating heart, recent advances such as multidetector arrays and subsecond gantry rotations have propelled CTA to a viable

Multimodality Imaging in Cardiovascular Medicine

routine modality, with current 3-dimensional (3D) resolution in the submillimeter range [93]. A recent assessment of atherosclerotic burden in 84 patients demonstrated good correlation between CTA and coronary angiography in the extremes of disease severity: ,50% and .90% stenosis. However, lesions consistent with a 50% to 90% stenosis by CTA did not correlate as strongly with coronary angiography, leading to the conclusion that additional assessment for myocardial ischemia would be useful before making decisions for revascularization [94]. Applicability of CTA for risk stratification in the postacute MI population remains limited. Because a .90% stenosis found on CTA is likely to lead to revascularization, the patient will be repeatedly exposed to ionizing radiation and nephrotoxic contrast during the subsequent coronary angiography and potential PCI. Lesions in the 50% to 90% range will likely need further physiologic assessment to assist in choosing revascularization or Â�medical management. While stenoses ,50% may not warrant revascularization, the pretest likelihood of no presence of lesions .50% in the post-MI population is very low. Myocardial Ischemia Identification of postacute MI ischemia, in either the periinfarct zone or in a remote zone, has important patient management implications. The SWISSI II trial randomly assigned 201 post-MI patients with silent ischemia and 1- or 2-vessel CAD to medical management or balloon angioplasty. Patients underwent a bicycle exercise protocol up to 3 months following acute MI. Those with asymptomatic ischemic ST changes on ECG underwent further evaluation by either echocardiographic or nuclear imaging techniques. During the 10-year follow-up, patients randomly assigned to PCI had fewer cardiac deaths (hazard ratio [HR] 0.19, confidence interval [CI] 0.05–0.67), fewer nonlethal MIs (HR 0.31, CI 0.15–0.65), and less angina (HR 0.48, CI 0.28–0.82) when compared to patients randomly assigned to medical therapy [95] (Figure 5.9). While LVEF did not change significantly in the PCI group, there was a significant decrease in LVEF from baseline to final follow-up time (59.7%  11.8% to 48.8%  7.9%, P , .001) in the medical management group [95]. Current guidelines provide a class I recommendation for all postacute MI patients to undergo further evaluation for myocardial ischemia [24,60]. Myocardial Viability Impaired LV function after acute MI and successful reperfusion therapy could be attributed to myocardial stunning or infarcted myocardium. Delayed recovery of myocardial function after prolonged ischemia has been observed up to 6 months after thrombolysis [96–98]. The dysfunction associated with stunning may be secondary to the prolonged effects of ischemia and/or reperfusion injury. Persistent postischemic myocardial contractile abnormalities in systolic

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F igure 5 . 9 â•… Fifteen-year event-free survival curves, in post–myocardial infarction (MI) patients identified with asymptomatic ischemia by stress

nuclear or echocardiography techniques within 3 months of the index MI. Patients were randomly assigned to medical therapy with or without percutaneous revascularization and followed up for clinical end points including cardiac death, nonfatal MI, and symptom-driven revascularization. There were significantly fewer events in patients undergoing percutaneous revascularization than those who received only medical management (P , .001). Reproduced with permission from Ref. 95.

and diastolic function have also been described after PCI, coronary artery bypass surgery, coronary vasospasm, and exercise [99–102]. Information from viability imaging in regions with impaired LV function, often combined with knowledge of the coronary anatomy from angiography, may be useful in determining the extent of myocardium at risk and assessing the likelihood that revascularization will result in an improvement in LV function, symptoms, or clinical outcomes. Viability imaging may be performed relatively early after MI or during the chronic stages, depending on the patient’s presentation, initial therapy, coronary anatomy, and clinical stability. Since most patients are treated with reperfusion therapy, often involving PCI, early identification of jeopardized myocardium may be important in only a selected subset of patients. Potential candidates for assessment of myocardial viability may include patients who are initially managed conservatively, present relatively late after infarction, have significant LV dysfunction, or have had primary coronary intervention (angioplasty or stent) but are suspected to have additional territories at risk. In such patients, assessment of myocardial viability and/or inducible myocardial ischemia may be appropriate. Parameters such as coronary artery patency [103–105], electrocardiographic Q waves [106,107], or regional LV contraction at rest [88,108–110] do not accurately predict myocardial viability. Myocardial viability is most commonly assessed with dobutamine echocardiography, nuclear imaging (MPI and/or metabolic imaging), and CMR (described above).

Dobutamine Stress Echocardiography The identification of viable myocardium with functional imaging rests on the principle that while contractile response may be abnormal at rest in hibernating or stunned myocardium, inotropic stimulation may demonstrate a contractile reserve, that is, an improvement in contractile response [111].

Experimental studies have shown that infarcted myocardium exhibits no change in function with dobutamine stress, whereas postischemic, dysfunctional but viable myocardium (defined by improvement in function over time) exhibits improved contraction during dobutamine infusion [112,113]. The stress protocol for viability studies using echocardiography typically utilizes assessment of function at both low and higher doses of dobutamine. A study by Smart and coworkers of patients within 7 days of thrombolytic therapy for acute MI emphasized the importance of the dose of dobutamine [114]. In their study, the response of wall motion in the infarct zone to low-dose dobutamine infusion (4 μg/kg/min) was sensitive and specific for identification of reversible dysfunction (sensitivity 86%, specificity 90%). Increasing doses of dobutamine that were large enough to affect hemodynamics, however, resulted in significantly decreased sensitivity. Thus, low-dose dobutamine echocardiography may be an accurate predictor of functional recovery after thrombolysis. The utility of echocardiography during dobutamine stimulation in predicting functional recovery following acute MI has been addressed by several investigators [114–117]. Data from these studies indicated that dobutamineresponsive improvement in LV wall motion not only is accurate in predicting functional recovery after revascularization [115,116] but also is useful in patients who are not revascularized [114,117]. Low-level exercise echocardiography may also be considered as an alternative to dobutamine stress. In a study comparing the 2 stressors directly in patients early after MI, low-level exercise echocardiography had comparable accuracy compared with dobutamine echocardiography [118]. An illustrative example of low-dose dobutamine and low-level exercise echocardiography is shown in Figure 5.10. The prognostic value of viability assessment using dobutamine stress echocardiography early after MI is not

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F igure 5 . 1 0 â•…End-diastolic (ED) and end-systolic (ES)

stop-frame echocardiograms obtained in a patient with inferior akinesis at rest (arrows), mild hypokinesis during low-level exercise echocardiography (LLEE), and normal thickening during low-dose dobutamine echocardiography (LDDE), and at follow-up (FU). Reprinted with permission from Ref. 118.

as clear. A number of studies, primarily in the thrombolytic era, have demonstrated conflicting data. Some studies indicate higher event rates in patients with significant viable myocardium [119–122], while others indicate lower event rates associated with viability [123,124]. Conflicting results of these studies may be related to the heterogeneous patient populations and study designs. In particular, most studies are not controlled for subsequent revascularization. Patients with significant myocardial viability who are not revascularized would be expected to have more cardiac events, and revascularization will have a significant impact on event rates in such patients.

Myocardial Contrast Echocardiography Echocardiography performed in conjunction with the injection of acoustically active gas-filled microspheres has been evaluated as a means to assess microvascular capillary integrity and myocardial perfusion. This technique is potentially useful for assessing myocardial viability since experimental studies suggest that intact microvasculature

5 . 1 1 â•…Representative end-systolic frames of myocardial contrast echocardiography in the apical 3-chamber view demonstrating lack of viability in a patient recently after acute myocardial infarction. Images show (A) akinetic mid-anterior septum and apex (arrows); (B) destruction of myocardial contrast immediately after a pulse; (C) lack of contrast opacification of the dysynergic segments, even after 15 cardiac cycles; and (D) lack of functional recovery at 12 weeks despite revascularization. Reprinted with permission from Ref. 127. F igure

is associated with viability. The initial intensity of microbubble contrast during steady state reflects capillary blood volume. These microbubbles can then be destroyed using pulses of high-energy ultrasound, and subsequent wash-in of microbubbles reflects myocardial blood velocity. Both measurements, that is, contrast intensity during steadystate and myocardial wash-in of contrast, can be used as indices of myocardial viability. Several studies have assessed the potential utility for myocardial contrast echocardiography to predict recovery of ventricular function after acute MI. In patients studied within 1 day to 4 weeks after acute MI with intracoronary injection of contrast, a good correlation was found between the contrast echo score, an index of intact perfusion, and regional functional improvement 1 month later [125]. Using intravenous contrast techniques, a number of studies have indicated that intact myocardial opacification early after MI predicts subsequent functional recovery [126,127]. Examples of a myocardial contrast echocardiography protocol are shown in Figures 5.11 and 5.12. Furthermore, poor opacification after infarction is associated with

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Figure 5.12â•…Representative end-systolic frames of myocardial Â�contrast echocardiography in the apical 3-chamber view demonstrating preserved viability in a patient recently after acute myocardial infarction. Images show (A) akinetic mid-septum, apex, and mid-lateral segments (arrows); (B) destruction of myocardial contrast immediately after a pulse; (C) homogenous contrast opacification of the dysynergic segments by 15 cardiac cycles; and (D) functional recovery at 12 weeks after revascularization. Reprinted with permission from Ref. 127.

adverse ventricular remodeling [128,129]. However, major limitations at present include the lack of outcomes data, as well as recent safety concerns regarding the use of echocardiographic contrast material early after MI or in patients with heart failure.

SPECT MPI for the Assessment of Myocardial Viability Many studies have addressed the utility of SPECT MPI in predicting myocardial viability, as defined by functional recovery in patients early after MI. MPI studies can be performed with thallium 201 or Tc 99m–based perfusion tracers (sestamibi and tetrofosmin). Modifications to the typical rest/stress acquisition protocols are needed, however, to achieve the best accuracy for viability assessment. Thallium MPI.â•… The initial uptake of thallium is proportional to myocardial blood flow, while its delayed uptake is dependent on the integrity of the sarcolemmal membrane. The clinical utility of thallium imaging for the assessment of myocardial viability in patients with chronic coronary artery disease is well established. Assessment with thallium may be performed in conjunction with exercise or pharmacologic stress testing [130–134] or with rest-redistribution thallium imaging alone [135–138]. The presence of viable myocardium is indicated by complete or partial improvement in thallium uptake on redistribution and/or reinjection imaging, or by the presence of mild to moderate persistent defects [138–140]. Rest-redistribution thallium imaging has been evaluated in patients with recent infarction. In patients with occluded infarct-related arteries, the absolute amount of myocardial activity present on delayed imaging correlates well with subsequent functional improvement [141]. In

first MI patients, a reversible component on thallium scanning performed 1 day after thrombolysis identified patients with significantly greater improvement in perfusion at day 10, indicating that rest-redistribution thallium imaging may identify residual ischemia very early after reperfusion [142]. Lack of improvement on thallium imaging after reperfusion is predictive of lack of improvement in function at 10 days to 3 months after infarction. Finally, the utility of rest-redistribution thallium imaging within 2  1 days after MI for prediction of functional recovery has been demonstrated [143]. Among the patients demonstrating myocardial viability in the infarct zone by thallium, the infarct-related artery was patent in all patients, and LV function improved significantly during follow-up. In contrast, in patients demonstrating lack of myocardial viability in the infarct zone by thallium, one-third of infarct-related arteries remained occluded, and LV function declined in this group over time [143]. Additional studies in larger number of patients are needed to assess the role of thallium imaging early after infarction. Tc 99m Perfusion Tracers.â•… Tc 99m perfusion tracers (sestamibi and tetrofosmin) are taken up by the myocardium in proportion to blood flow at normal or moderately elevated flow rates. These tracers have similar physical and biological properties. Related to viability assessment, while the initial uptake of these tracers is related to myocardial perfusion, the accumulation and retention of the tracers is related to energy-dependent processes in viable myocytes, which maintain membrane polarization. Thus, the myocardial retention of Tc 99m perfusion Â�tracers is a marker of cellular viability, which has been demonstrated in experimental models of MI with and without reperfusion [66,144].

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Similar to thallium studies, most of the data on viability assessment with Tc 99m perfusion tracers have been obtained in patients with chronic CAD and healed prior MI. The initial experience with Tc 99m perfusion tracers suggested that they underestimate defect reversibility and myocardial viability in patients with chronic coronary artery disease [145–155]. The potential underestimation of viability may be particularly evident in regions with severe dysfunction or regions supplied by severely stenosed arteries. Several modifications to the routine rest-stress protocol have emerged that improve the accuracy of sestamibi or tetrofosmin imaging for the assessment of myocardial viability. These include quantification of perfusion defect severity [156], nitrate-enhanced rest imaging [157–163], combined assessment of perfusion and function with gated SPECT [164], addition of low-dose dobutamine-gated SPECT [165], and the use of attenuation correction techniques [166]. Dual-isotope imaging is another method that can be used to take advantage of the favorable perfusion imaging characteristics of Tc 99m–based tracers and the enhanced viability detection of thallium. This method combines rest-redistribution thallium with stress sestamibi. Using appropriate modifications to acquisition parameters, viability assessment with Tc 99m–based tracers may perform as well as thallium for assessment of viability (Figure 5.13).

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Clinical studies concerning viability assessment with sestamibi early after MI have focused on the approach of determination of degree of myocardial salvage and final infarct size, as discussed above. However, to date, there are no conclusive studies examining the assessment of sestamibi as a viability tracer specifically in a population of patients early after MI.

Metabolic Imaging with PET and SPECT The metabolic and structural alterations in stunned myocardium are incompletely understood. The major structural changes that have been observed are disruptions of the contractile elements, including myofibrillar loss and disarray, accumulation of glycogen, and changes to many cytoplasmic and nuclear substructures. Mechanisms that may contribute include free-radical injury [167], microvascular accumulation of neutrophils in previously ischemic tissue [168], and impairment of sympathetic nerve activity as a result of ischemic damage [169]. From a metabolic standpoint, myocardial ischemia causes an initial decline in glucose uptake during the acute ischemic episode, followed by a rapid return to baseline [170] or increase above baseline [171] during early reperfusion. The metabolic fate of increased glucose uptake remains unclear; possible explanations include glycogen repletion and/or a transient shift to anaerobic metabolism. Fatty acid oxidation may be depressed under conditions of hypoxia and ischemia and may remain depressed early after reperfusion. Based on these physiological principles, metabolic imaging, using fatty acid or glucose analogs, may be used to assess myocardial ischemia and viability.

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F igure 5 . 1 3 â•…Receiver operating characteristic curves demonstrating the sensitivity-specificity pairs for the Tc 99m–based perfusion tracers (sestamibi and tetrofosmin) compared to thallium. Protocols included nitrate-enhanced rest imaging, and all tracers show comparable accuracy for predicting functional recovery of akinetic or dyskinetic segments after revascularization procedures. Reprinted with permission from Ref. 157.

[18F]2-Deoxy,2-fluoroglucose Imaging with PET.â•… In patients with chronic CAD, viable myocardium by PET is usually defined on the basis of preserved or enhanced myocardial metabolic substrate utilization as assessed by [18F]2-deoxy, 2-fluoroglucose (FDG). The utility of FDG PET in the early post-MI period has been addressed in a small number of studies and was first described by Marshall and colleagues [172]. Among regions with resting hypoperfusion, 2 patterns of tracer uptake were identified—a concordant reduction in both flow and metabolism (termed a flow-metabolism match), which was considered to represent myocardial scar, and a discordant increase in FDG uptake compared to flow (termed a flow-metabolism mismatch), which was considered to represent ischemic, viable myocardium (Figure 5.14). Patients with flow-metabolism mismatch were more likely to have had postinfarction angina at rest and more extensive coronary artery disease than those without mismatch. This study established the potential utility of glucose metabolic imaging for the identification of viable myocardium early after MI.

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F igure 5 . 1 4 â•…Positron emission tomography scan showing perfusion (top)-metabolism (bottom) mismatch in hibernating heart as an example of pre-

served cardiometabolic reserve. Rubidium 82 positron emission tomograms in short-axis view (top row) show markedly decreased perfusion defects in the apical, inferior, inferolateral, and septal regions of the left Â�ventricle at rest, which extends from distal to basal slices. [18F]2-deoxy, 2-fluoroglucose (FDG) images acquired under glucose-loaded condition (lower row) show perfusion-metabolism mismatch pattern (the scintigraphic hallmark of hibernation) in all abnormally perfused myocardial regions at rest, with exception of the anteroseptal region, which demonstrates a matched perfusion-metabolism pattern (compatible with scarred myocardium). From Ref. 176.

Several subsequent studies investigated PET imaging early after MI. Schwaiger and colleagues studied 13 patients within 72 hours of MI with 13N ammonia/FDG PET and subsequent serial assessment of LV function [173]. PET was performed 54  12 hours after the onset of chest pain. They reported no change in regional function over time (mean 6 weeks) in myocardial segments with concordant decreases in both flow and metabolism, consistent with nonviable myocardium. In segments with flow-metabolism mismatch (ie, reduced flow and preserved metabolism), however, only 50% of such regions showed recovery of function. Thus, in patients studied with FDG very soon after MI, the absence of FDG activity appears to accurately predict nonviable myocardium, whereas the presence of FDG activity may not be a reliable indicator of viability and subsequent functional recovery. The presence of FDG uptake, however, does appear to be associated with residual antegrade flow in the infarct-related artery [174], which may have beneficial clinical effects independent of functional recovery. However, the timing of PET imaging may be quite important in the postinfarction period. In another study by Pierard et al [116], when PET images were acquired within 9  7 days of admission, improved infarct-zone regional contraction was observed in 10 of 11 patients with viable pattern by PET, and no such improvement in the 6 patients with infarct pattern by PET. In addition, late functional recovery (9  7 months later) was observed in all patients with viable pattern by PET compared to 1 of 6 patients with infarct pattern by PET. Thus, metabolic imaging with FDG PET approximately 1 week after acute MI appears to correlate with functional reserve and late functional recovery in such patients.

Fatty Acid Imaging with BMIPP SPECT.â•… An exciting development in this field is the use of the radioiodine-labeled branched-chain fatty acid [123I]-b-methyl-p-iodophenylpentadecanoic acid (BMIPP) for the assessment of fatty acid metabolism with SPECT. Decrease and subsequent delayed recovery of fatty acid metabolism, long after regional blood flow has returned to baseline was previously shown with BMIPP. This was termed ischemic memory to indicate the imprint of the antecedent ischemic event [175,176]. Experimental studies indicate the potential utility of these fatty acid tracers for the assessment of myocardial viability early after MI. Miller and colleagues investigated the relationship between BMIPP uptake and myocardial blood flow and histochemical delineation of infarction in an occlusionreperfusion dog model [177]. In both the occluded and reperfused state, BMIPP uptake was higher than blood flow in regions with preserved viability by histochemical staining. In a subgroup of dogs, BMIPP uptake exceeded thallium uptake in viable segments. Several studies have suggested the utility of an approach in which fatty acid uptake is compared to a blood flow tracer in patients with prior MI. Tamaki and colleagues studied a group of patients within 4 weeks of infarction with BMIPP and thallium and found that a significant number of patients had mismatch between blood flow and BMIPP uptake, consistent with viable myocardium [178]. Kawamoto and coworkers subsequently studied 22 patients with recent MI with BMIPP and thallium SPECT, a subgroup of whom had FDG PET [179]. In this study, myocardial segments with less BMIPP uptake than stress thallium uptake (discordant segments) were more likely to have thallium redistribution and/or increased FDG uptake

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compared to segments with comparable BMIPP and thallium uptake. These studies suggest that metabolic imaging with fatty acid analogs, combined with assessment of myocardial blood flow, may be useful for the assessment of viable, recently injured myocardium. Predicting Sudden Cardiac Death and Benefit of Implantable Cardiac Defibrillators There are more than 300 000 annual SCDs in North America, the vast majority of which are secondary to CAD and/or prior MI [180]. Although SCD risk is highest during and immediately after an infarction, only 25% of deaths occur in the first 3 months and 50% within the first year following MI [181,182]. LV Systolic Function LV dysfunction or reduced LVEF is one of the most powerful variables linked to cardiac mortality due to arrhythmias and SCD [183]. The relationship between SCD and LV dysfunction was well studied in a post hoc analysis from the VALIANT trial [182]. Of the nearly 14 000 patients enrolled, 77% had LVEF determined prior to discharge—81% by echocardiography, 17% by contrast ventriculography, and 2% by radionuclide Â�ventriculography. Within the first 30 days post-MI, 34% of patients with LVEF ,30% had the highest rates of Â�sudden or resuscitated cardiac death (2.3% per month; 95% CI 1.8%–2.8%). Each 5% decrease in LVEF Â�correlated with a 21% increase in SCD risk. As LVEF is such a potent predictor of SCD in the post-MI patient, primary prevention of SCD with use of implantable cardiac defibrillator (ICD) devices is now recommended. Using LVEF as the sole prognostic Â�factor, the MADIT II trial assessed prophylactic ICD use in post-MI patients with an LVEF <30% and Â�demonstrated reduced 2-year SCD rates in the ICD group as compared to conventional medical therapy (4.9% vs. 12.1%, P , .0001) [184]. With this and other trial data, the 2008 ACC/AHA/ HRS guidelines for device-based therapy provide a class I indication for ICD therapy in post-MI patients with LVEF ,30% (or LVEF ,35% and NYHA class II–III HF symptoms) at least 40 days beyond the index event [185]. The guideline committee recognizes the lack of a gold standard for determining LVEF and suggests use of the institution’s imaging modality with highest accuracy and clinical appropriateness, per the physician’s discretion. As found in VALIANT and other studies, approximately two-thirds of post-MI patients do not have severely depressed LV systolic function (LVEF ,30%) [182,186]. While the individual risk for SCD is highest in low LVEF patients, the overall number of SCD events remains high in the post-MI patients with preserved LVEF. Accordingly, occurrence of ventricular arrhythmias and SCD after MI

Multimodality Imaging in Cardiovascular Medicine

does not solely depend on LVEF, but is likely due to interactions of various other factors. Independent of LVEF, the presence of inducible VT detected by an electrophysiology study is also associated with increased risk of SCD [187]. Because electrophysiologic studies are invasive, noninvasive cardiac imaging modalities are being developed to further characterize the relationship of SCD to other variables, such as residual or potential myocardial ischemia, characteristics of myocardial scar, and impaired autonomic modulation. Residual or Potential Myocardial Ischemia Residual myocardial ischemia following MI may also be a marker of increased risk of SCD. Paganelli and colleagues investigated the effect of residual myocardial ischemia on inducible ventricular arrhythmias during programed stimulation. Ninety MI survivors were assessed for inducible ventricular tachyarrhythmia by electrophysiology study and residual myocardial ischemia by thallium SPECT imaging. Myocardial ischemia was more frequently found in patients with inducible arrhythmias than in those without (42.5% vs. 25.7%, P , .05) [188]. Additional prospective studies are needed to determine if revascularization or medical alleviation of the ischemic burden decreases the risk of SCD or if AICD therapy is indicated in this patient population. Myocardial Scar/Tissue Heterogeneity Infarcted myocardial tissue or scar is a substrate for malignant reentrant arrhythmias [189–191]. This is in part due to a heterogeneous distribution of viable cardiomyocytes interspersed within areas of necrosis, particularly in peripheral zones of infarcted tissue [192–194]. Characterization of peri-infarct tissue heterogeneity by contrast-enhanced MRI is a potential future tool for further risk stratification. In a cohort of 47 post-MI patients referred for ICD therapy, inducible sustained monomorphic VT was correlated with tissue heterogeneity and other LV measures obtained by contrast-enhanced MRI. Extensive tissue heterogeneity on contrast-enhanced MRI was strongly associated with electrical instability while LVEF, LV end-diastolic volume, and infarct size were not [195]. The efficacy of myocardial scar and tissue heterogeneity assessment for providing prognostic information and predicting SCD requires further investigation. Myocardial Innervation Myocardial contractility is balanced by input from the sympathetic and the parasympathetic nerve fibers. The parasympathetic nervous system has a negative chronotropic effect as compared to the sympathetic system, which has both Â�positive inotropic and chronotropic effects. Sympathetic

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overactivity and parasympathetic withdrawal, resulting from MI and ventricular remodeling, are associated with increased ventricular arrhythmias and SCD [196]. To predict arrhythmias and SCD, various radiopharmaceutical agents have been developed to evaluate cardiac innervation. 123 I-metaiodobenzylguanidine (mIBG), is a guanethidine analog, which shares the same reuptake mechanism and endogenous storage with norepinephrine, but it is neither metabolized nor does it interact with postsynaptic receptors. mIBG has not been approved as of yet by the US Food and Drug Administration. Nonetheless, a number of small and single-center studies, using both planar and SPECT imaging, have reported dissociation between myocardial perfusion, metabolism, and innervations [197,198]. mIBG imaging parameters of heart-tomediastinal ratio and washout rates from the myocardium have been compared with the various electrophysiological indices for predicting arrhythmias and SCD in postMI patients. In 106 patients (52% post-MI) with LVEF ,40%, cardiac mIBG imaging parameters were compared with signal-averaged electrocardiogram(, heart rate variability, and QT dispersion. Along with LVEF, mIBG washout rate (prevalence 5 27%) was shown to be independently associated with SCD (HR 4.79, 95% CI 1.55–14.76, P 5 .004) [199]. Other myocardial innervation radiotracers, such as C 11–labeled hydroxyephedrine and epinephrine are also being studied using PET imaging. While these new noninvasive nuclear techniques that assess myocardial innervations are encouraging, they remain investigational until larger prospective trials are undertaken to establish their role in clinical practice.

j â•… CONCLUSION Given the multitude of noninvasive modalities available for the practicing physician, it is very important to determine when to order tests for either diagnostic or Â�prognostic purposes. In the acute phase of MI, global and regional LV dysfunction may represent both stunned and irreversibly injured myocardium. Among patients with multivessel CAD and an acute infarction, LV dysfunction can be a manifestation of both stunned (reperfused myocardium in the infarct zone) and hibernating (remote asynergy to the infarct zone) myocardium. MPI in this setting can provide information on the degree of myocardial salvage post-reperfusion therapy and the amount of viable and scarred myocardium that is responsible for the LV dysfunction in the subacute phase of infarction. Rest MPI (with redistribution for thallium) can aid to differentiate viable (stunned and/or hibernating regions) from nonviable (acute necrosis and/or prior scar) myocardium. Patients with severe regional wall motion abnormalities and global LV dysfunction who manifest

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preserved Â�radiotracer uptake in these asynergic regions have considerable myocardium that is viable. Such asynergic regions with preserved radiotracer uptake (at least 50% of peak in the normal zone) on rest MPI show improved systolic Â�function after revascularization. On the other hand, asynergic regions with severely decreased perfusion defects (less than 50% of peak uptake) are unlikely to benefit from revascularization. At the time of hospital discharge, stress MPI (beyond rest images in the acute phase) can best Â�separate high- and low-risk patients. Echocardiography and CMR can also be used in this setting for the assessment of residual viability in asynergic myocardial regions when used in conjunction with low-dose dobutamine. While delayed-enhanced CMR is highly accurate in defining the extent of scar, it is important to recognize that infarcts involute over time such that there is a 25% to 30% decrease in DE-CMR infarct size from the first week to the chronic phase of infarction. Cardiac CT is an emerging technique, with limited data concerning its role for assessment of MI and salvage in the setting of acute MI. In the future, emerging techniques of assessing myocardial scar/tissue Â�heterogeneity by contrast-enhanced CMR and myocardial innervation with SPECT may identify the subset of postacute MI patients who are at risk for SCD and who may Â�benefit from ICDs.

jâ•… REF ERENCES â•… 1. Lloyd-Jones D, Adams R, Carnethon M, et al. Heart disease and stroke statistics—2009 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. January 27, 2009;119(3):480–486. â•… 2. Rea TD, Pearce RM, Raghunathan TE, et al. Incidence of out-ofhospital cardiac arrest.Am J Cardiol. June 15,2004;93(12):1455–1460. â•… 3. Kung HC, Hoyert DL, Xu J, et al. Deaths: final data for 2005. Natl Vital Stat Rep. April 24,2008;56(10):1–120. â•… 4. Becker RC, Burns M, Gore JM, et al. Early assessment and inhospital management of patients with acute myocardial infarction at increased risk for adverse outcomes: a nationwide perspective of current clinical practice. The National Registry of Myocardial Infarction (NRMI-2) Participants. Am Heart J. May 1998;135 (5, pt 1):786–796. â•… 5. Beygui F, Collet JP, Benoliel JJ, et al. High plasma aldosterone levels on admission are associated with death in patients presenting with acute ST-elevation myocardial infarction. Circulation. December 12, 2006;114(24):2604–2610. â•… 6. Califf RM, Pieper KS, Lee KL, et al. Prediction of 1-year survival after thrombolysis for acute myocardial infarction in the global utilization of streptokinase and TPA for occluded coronary arteries trial. Circulation. May 16, 2000;101(19):2231–2238. â•… 7. Giannitsis E, Muller-Bardorff M, Lehrke S, et al. Admission troponin T level predicts clinical outcomes, TIMI flow, and myocardial tissue perfusion after primary percutaneous intervention for acute ST-segment elevation myocardial infarction. Circulation. August 7, 2001;104(6):630–635. â•… 8. Kanna M, Nonogi H, Sumida H, et al. Usefulness of serum troponin T levels on day three or four in predicting survival after acute myocardial infarction. Am J Cardiol. February 1, 2001;87(3):294–297.

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86

â•… 9. Khan SQ, Quinn P, Davies JE, et al. N-terminal pro-B-type natriuretic peptide is better than TIMI risk score at predicting death after acute myocardial infarction. Heart. January 2008;94(1):40–43. â•‡ 10. Mega JL, Morrow DA, De Lemos JA, et al. B-type natriuretic peptide at presentation and prognosis in patients with ST-segment elevation myocardial infarction: an ENTIRE-TIMI-23 substudy. J Am Coll Cardiol. July 21, 2004;44(2):335–339. â•‡ 11. Ohman EM, Armstrong PW, White HD, et al. Risk stratification with a point-of-care cardiac troponin T test in acute myocardial infarction. GUSTOIII Investigators. Global Use of Strategies To Open Occluded Coronary Arteries. Am J Cardiol. December 1, 1999;84(11):1281–1286. â•‡ 12. Omland T, Aakvaag A, Bonarjee VV, et al. Plasma brain natriuretic peptide as an indicator of left ventricular systolic function and longterm survival after acute myocardial infarction. Comparison with plasma atrial natriuretic peptide and N-terminal proatrial natriuretic peptide. Circulation. June 1, 1996;93(11):1963–1969. â•‡ 13. Omland T, Persson A, Ng L, et al. N-terminal pro-B-type natriuretic peptide and long-term mortality in acute coronary syndromes. Circulation. December 3, 2002;106(23):2913–2918. â•‡ 14. Ottani F, Galvani M, Nicolini FA, et al. Elevated cardiac troponin levels predict the risk of adverse outcome in patients with acute coronary syndromes. Am Heart J. December 2000;140(6):917–927. â•‡ 15. Richards AM, Nicholls MG, Espiner EA, et al. B-type natriuretic peptides and ejection fraction for prognosis after myocardial infarction. Circulation. June 10, 2003;107(22):2786–2792. â•‡ 16. Richards AM, Nicholls MG, Yandle TG, et al. Plasma N-terminal probrain natriuretic peptide and adrenomedullin: new neurohormonal predictors of left ventricular function and prognosis after myocardial infarction. Circulation. May 19, 1998;97(19):1921–1929. â•‡ 17. Savonitto S, Granger CB, Ardissino D, et al. The prognostic value of creatine kinase elevations extends across the whole spectrum of acute coronary syndromes. J Am Coll Cardiol. January 2, 2002;39(1):22–29. â•‡ 18. Tapanainen JM, Lindgren KS, Makikallio TH, et al. Natriuretic peptides as predictors of non-sudden and sudden cardiac death after acute myocardial infarction in the beta-blocking era. J Am Coll Cardiol. March 3, 2004;43(5):757–763. â•‡ 19. Evaluation of patients after recent acute myocardial infarction. American College of Physicians. Ann Intern Med. March 15, 1989;110(6):485–488. â•‡ 20. Norris RM, Barnaby PF, Brandt PW, et al. Prognosis after recovery from first acute myocardial infarction: determinants of reinfarction and sudden death. Am J Cardiol. February 1, 1984;53(4):408–413. â•‡ 21. Lowe JE, Reimer KA, Jennings RB. Experimental infarct size as a function of the amount of myocardium at risk. Am J Pathol. February 1978;90(2):363–379. â•‡ 22. Reimer KA, Jennings RB, Cobb FR, et al. Animal models for protecting ischemic myocardium: results of the NHLBI Cooperative Study. Comparison of unconscious and conscious dog models. Circ Res. May 1985;56(5):651–665. â•‡ 23. Topol EJ, Ellis SG. Coronary collaterals revisited. Accessory pathway to myocardial preservation during infarction. Circulation. March 1991;83(3):1084–1086. â•‡ 24. Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines (Committee to revise the 1999 guidelines for the management of patients with acute myocardial infarction). Circulation. August 31, 2004;110(9):e82–e292. â•‡ 25. Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-Elevation myocardial infarction: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines (Writing Committee to revise the 2002 guidelines for the management of patients with unstable angina/non-ST-Elevation myocardial infarction) developed in collaboration with the American College of

â•‡ 26.

â•‡ 27.

â•‡ 28.

â•‡ 29.

â•‡ 30.

â•‡ 31.

â•‡ 32.

â•‡ 33.

â•‡ 34.

â•‡ 35.

â•‡ 36.

â•‡ 37.

â•‡ 38.

â•‡ 39.

â•‡ 40.

â•‡ 41.

â•‡ 42.

Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. J Am Coll Cardiol. August 14, 2007;50(7):e1–e157. De Luca G, Suryapranata H, van’t Hof AW, et al. Prognostic assessment of patients with acute myocardial infarction treated with primary angioplasty: implications for early discharge. Circulation. June 8, 2004;109(22):2737–2743. Halkin A, Singh M, Nikolsky E, et al. Prediction of mortality after primary percutaneous coronary intervention for acute myocardial infarction: the CADILLAC risk score. J Am Coll Cardiol. May 3, 2005;45(9):1397–1405. Eagle KA, Lim MJ, Dabbous OH, et al. A validated prediction model for all forms of acute coronary syndrome: estimating the risk of 6-month postdischarge death in an international registry. JAMA. June9, 2004;291(22):2727–2733. Morrow DA, Antman EM, Charlesworth A, et al. TIMI risk score for ST-elevation myocardial infarction: a convenient, bedside, clinical score for risk assessment at presentation: an intravenous nPA for treatment of infarcting myocardium early II trial substudy. Circulation. 2000;102(17):2031–2037. Morrow DA, Antman EM, Giugliano RP, et al. A simple risk index for rapid initial triage of patients with ST-elevation myocardial infarction: an In TIME II substudy. Lancet. November 10, 2001;358(9293):1571–1575. Cannon CP. Evidence-based risk stratification to target therapies in acute coronary syndromes. Circulation. September 24, 2002;106(13):1588–1591. Cannon CP, Weintraub WS, Demopoulos LA, et al. Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor tirofiban. N Engl J Med. June 21, 2001;344(25):1879–1887. Dodge HT, Sandler H, Ballew DW, et al. The use of biplane angiocardiography for the measurement of left ventricular volume in man. Am Heart J. November 1960;60:762–776. Taylor GJ, Humphries JO, Mellits ED, et al. Predictors of clinical course, coronary anatomy and left ventricular function after recovery from acute myocardial infarction. Circulation. November 1980;62(5):960–970. White HD, Norris RM, Brown MA, et al. Left ventricular end-Â� systolic volume as the major determinant of survival after recovery from myocardial infarction. Circulation. July 1987;76(1):44–51. Gheorghiade M, Ruzumna P, Borzak S, et al. Decline in the rate of hospital mortality from acute myocardial infarction: impact of changing management strategies. Am Heart J. February 1996;131(2):250–256. Braunwald E, Kloner RA. The stunned myocardium: prolonged, postischemic ventricular dysfunction. Circulation. December 1982;66(6):1146–1149. Ndrepepa G, Mehilli J, Martinoff S, et al. Evolution of left ventricular ejection fraction and its relationship to infarct size after acute myocardial infarction. J Am Coll Cardiol. July 10, 2007;50(2):149–156. Sheehan FH, Doerr R, Schmidt WG, et al. Early recovery of left ventricular function after thrombolytic therapy for acute myocardial infarction: an important determinant of survival. J Am Coll Cardiol. August 1988;12(2):289–300. Solomon SD, Glynn RJ, Greaves S, et al. Recovery of ventricular function after myocardial infarction in the reperfusion era: the healing and early afterload reducing therapy study. Ann Intern Med. March 20, 2001;134(6):451–458. Engblom H, Hedstrom E, Heiberg E, et al. Rapid initial reduction of hyperenhanced myocardium after reperfused first myocardial infarction suggests recovery of the peri-infarction zone: one-year follow-up by MRI. Circ Cardiovasc Imaging. January 2009;2(1):47–55. Gardner BI, Bingham SE, Allen MR, et al. Cardiac magnetic resonance versus transthoracic echocardiography for the assessment of cardiac volumes and regional function after myocardial infarction:

C HAP T ER 5

â•‡ 43.

â•‡ 44.

â•‡ 45.

â•‡ 46.

â•‡ 47.

â•‡ 48.

â•‡ 49. â•‡ 50.

â•‡ 51.

â•‡ 52.

â•‡ 53.

â•‡ 54.

â•‡ 55.

â•‡ 56.

â•‡ 57.

â•‡ 58.

â•‡ 59.

•

Post-MI Risk Stratification

an intrasubject comparison using simultaneous intrasubject recordings. Cardiovasc Ultrasound. 2009;7:38. Teichholz LE, Kreulen T, Herman MV, et al. Problems in echocardiographic volume determinations: echocardiographic-Â�angiographic correlations in the presence of absence of asynergy. Am J Cardiol. January 1976;37(1):7–11. Grothues F, Smith GC, Moon JC, et al. Comparison of interstudy reproducibility of cardiovascular magnetic resonance with twodimensional echocardiography in normal subjects and in patients with heart failure or left ventricular hypertrophy. Am J Cardiol. July 1, 2002;90(1):29–34. Otterstad JE, Froeland G, St John Sutton M, et al. Accuracy and reproducibility of biplane two-dimensional echocardiographic measurements of left ventricular dimensions and function. Eur Heart J. March 1997;18(3):507–513. Moller JE, Hillis GS, Oh JK, et al. Wall motion score index and ejection fraction for risk stratification after acute myocardial infarction. Am Heart J. February 2006;151(2):419–425. Moller JE, Whalley GA, Dini FL, et al. Independent prognostic importance of a restrictive left ventricular filling pattern after myocardial infarction: an individual patient meta-analysis: MetaAnalysis Research Group in Echocardiography acute myocardial infarction. Circulation. May 20, 2008;117(20):2591–2598. Grigioni F, Enriquez-Sarano M, Zehr KJ, et al. Ischemic mitral regurgitation: long-term outcome and prognostic implications with quantitative Doppler assessment. Circulation. April 3 2001;103 (13):1759–1764. Risk stratification and survival after myocardial infarction. N Engl J Med. August 1,1 1983;309(6):331–336. Bonow RO. Prognostic assessment in coronary artery disease: role of radionuclide angiography. J Nucl Cardiol. May-June 1994;1(3):280–291. Califf RM, Topol EJ, Gersh BJ. From myocardial salvage to patient salvage in acute myocardial infarction: the role of reperfusion therapy. J Am Coll Cardiol. November 1, 1989;14(5):1382–1388. Zaret BL, Wackers FJ, Terrin ML, et al. Assessment of global and regional left ventricular performance at rest and during exercise after thrombolytic therapy for acute myocardial infarction: results of the thrombolysis in myocardial infarction (TIMI) II study. Am J Cardiol. January 1, 1992;69(1):1–9. Simoons ML, Vos J, Tijssen JG, et al. Long-term benefit of early thrombolytic therapy in patients with acute myocardial infarction: 5 year follow-up of a trial conducted by the Interuniversity Cardiology Institute of The Netherlands. J Am Coll Cardiol. December 1989;14(7):1609–1615. Burns RJ, Gibbons RJ, Yi Q, et al. The relationships of left ventricular ejection fraction, end-systolic volume index and infarct size to six-month mortality after hospital discharge following myocardial infarction treated by thrombolysis. J Am Coll Cardiol. January 2, 2002;39(1):30–36. Kroll D, Farah W, McKendall GR, et al. Prognostic value of stressgated Tc-99m sestamibi SPECT after acute myocardial infarction. Am J Cardiol. February 15, 2001;87(4):381–386. Mahmarian JJ, Mahmarian AC, Marks GF, et al. Role of adenosine thallium-201 tomography for defining long-term risk in patients after acute myocardial infarction. J Am Coll Cardiol. May 1995;25(6):1333–1340. Miller TD, Christian TF, Hopfenspirger MR, et al. Infarct size after acute myocardial infarction measured by quantitative tomographic 99mTc sestamibi imaging predicts subsequent mortality. Circulation. August 1, 1995;92(3):334–341. Silverman KJ, Becker LC, Bulkley BH, et al.Value of early Â�thallium-201 scintigraphy for predicting mortality in patients with acute myocardial infarction. Circulation. May 1980;61(5):996–1003. Travin MI, Dessouki A, Cameron T, et al. Use of exercise Â�technetium-99m sestamibi SPECT imaging to detect residual ischemia and for risk stratification after acute myocardial infarction. Am J Cardiol. April, 1 1995;75(10):665–669.

87

â•‡ 60. Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/ non-ST elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to revise the 2002 guidelines for the management of patients with unstable angina/non ST-elevation myocardial infarction): developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons: endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. Circulation. August 14, 2007;116(7):e148–e304. â•‡ 61. Abraham RD, Harris PJ, Roubin GS, et al. Usefulness of ejection fraction response to exercise one month after acute myocardial infarction in predicting coronary anatomy and prognosis. Am J Cardiol. August 1, 1987;60(4):225–230. â•‡ 62. Morris KG, Palmeri ST, Califf RM, et al. Value of radionuclide angiography for predicting specific cardiac events after acute myocardial infarction. Am J Cardiol. February 1, 1985;55(4):318–324. â•‡ 63. Gibson RS, Watson DD, Craddock GB, et al. Prediction of cardiac events after uncomplicated myocardial infarction: a prospective study comparing predischarge exercise thallium-201 scintigraphy and coronary angiography. Circulation. August 1983;68(2):321–336. â•‡ 64. De Coster PM, Melin JA, Detry JM, et al. Coronary artery reperfusion in acute myocardial infarction: assessment by pre- and postintervention thallium-201 myocardial perfusion imaging. Am J Cardiol. April 1, 1985;55(8):889–895. â•‡ 65. Reduto LA, Freund GC, Gaeta JM, et al. Coronary artery reperfusion in acute myocardial infarction: beneficial effects of intracoronary streptokinase on left ventricular salvage and performance. Am Heart J. December 1981;102(6, pt 2):1168–1177. â•‡ 66. Sinusas AJ, Trautman KA, Bergin JD, et al. Quantification of area at risk during coronary occlusion and degree of myocardial salvage after reperfusion with technetium-99m methoxyisobutyl isonitrile. Circulation. October 1990;82(4):1424–1437. â•‡ 67. Verani MS, Jeroudi MO, Mahmarian JJ, et al. Quantification of myocardial infarction during coronary occlusion and myocardial salvage after reperfusion using cardiac imaging with technetium99m hexakis 2-methoxyisobutyl isonitrile. J Am Coll Cardiol. December 1988;12(6):1573–1581. â•‡ 68. Christian TF, Behrenbeck T, Pellikka PA, et al. Mismatch of left ventricular function and infarct size demonstrated by technetium-99m isonitrile imaging after reperfusion therapy for acute myocardial infarction: identification of myocardial stunning and hyperkinesia. J Am Coll Cardiol. December 1990;16(7):1632–1638. â•‡ 69. Christian TF, Gibbons RJ, Gersh BJ. Effect of infarct location on myocardial salvage assessed by technetium-99m isonitrile. J Am Coll Cardiol. May 1991;17(6):1303–1308. â•‡ 70. Behrenbeck T, Pellikka PA, Huber KC, et al. Primary angioplasty in myocardial infarction: assessment of improved myocardial perfusion with technetium-99m isonitrile. J Am Coll Cardiol. February 1991;17(2):365–372. â•‡ 71. Santoro GM, Bisi G, Sciagra R, et al. Single photon emission computed tomography with technetium-99m hexakis 2-methoxyisobutyl isonitrile in acute myocardial infarction before and after thrombolytic treatment: assessment of salvaged myocardium and prediction of late functional recovery. J Am Coll Cardiol. February 1990;15(2): 301–314. â•‡ 72. Hundley WG, Morgan TM, Neagle CM, et al. Magnetic resonance imaging determination of cardiac prognosis. Circulation. October 29, 2002;106(18):2328–2333. â•‡ 73. Semelka RC, Tomei E, Wagner S, et al. Interstudy reproducibility of dimensional and functional measurements between cine magnetic resonance studies in the morphologically abnormal left ventricle. Am Heart J. June 1990;119(6):1367–1373. â•‡ 74. Semelka RC, Tomei E, Wagner S, et al. Normal left ventricular dimensions and function: interstudy reproducibility of

Multimodality Imaging in Cardiovascular Medicine

88

â•‡ 75. â•‡ 76.

â•‡ 77.

â•‡ 78.

â•‡ 79.

â•‡ 80.

â•‡ 81.

â•‡ 82.

â•‡ 83.

â•‡ 84.

â•‡ 85.

â•‡ 86.

â•‡ 87.

â•‡ 88.

â•‡ 89.

â•‡ 90.

â•‡ 91.

â•‡ 92.

measurements with cine MR imaging. Radiology. March 1990;174 (3, pt 1):763–768. Pohost GM, Hung L, Doyle M. Clinical use of cardiovascular magnetic resonance. Circulation. August 12, 2003;108(6):647–653. Wagner A, Mahrholdt H, Holly TA, et al. Contrast-enhanced MRI and routine single photon emission computed tomography (SPECT) perfusion imaging for detection of subendocardial myocardial infarcts: an imaging study. Lancet. February 1. 2003;361(9355):374–379. Choi KM, Kim RJ, Gubernikoff G, et al. Transmural extent of acute myocardial infarction predicts long-term improvement in contractile function. Circulation. September 4, 2001;104(10):1101–1107. Lima JA, Judd RM, Bazille A, et al. Regional heterogeneity of human myocardial infarcts demonstrated by contrast-enhanced MRI. Potential mechanisms. Circulation. September 1, 1995;92(5):1117–1125. Wu KC, Zerhouni EA, Judd RM, et al. Prognostic significance of microvascular obstruction by magnetic resonance imaging in patients with acute myocardial infarction. Circulation. March 3, 1998;97(8):765–772. Kim RJ, Fieno DS, Parrish TB, et al. Relationship of MRI delayed contrast enhancement to irreversible injury, infarct age, and contractile function. Circulation. November 9, 1999;100(19):1992–2002. Fieno DS, Kim RJ, Chen EL, et al. Contrast-enhanced magnetic Â�resonance imaging of myocardium at risk: distinction between reversible and irreversible injury throughout infarct healing. J Am Coll Cardiol. November 15, 2000;36(6):1985–1991. Rehwald WG, Fieno DS, Chen EL, et al. Myocardial magnetic resonance imaging contrast agent concentrations after reversible and irreversible ischemic injury. Circulation. January 15, 2002;105(2):224–229. Gerber BL, Garot J, Bluemke DA, et al. Accuracy of contrastenhanced magnetic resonance imaging in predicting improvement of regional myocardial function in patients after acute myocardial infarction. Circulation. August 27, 2002;106(9):1083–1089. Beek AM, Kuhl HP, Bondarenko O, et al. Delayed contrast-enhanced magnetic resonance imaging for the prediction of regional functional improvement after acute myocardial infarction. J Am Coll Cardiol. September 3, 2003;42(5):895–901. Bruder O, Breuckmann F, Jensen C, et al. Prognostic impact of Â�contrast-enhanced CMR early after acute ST segment elevation myocardial infarction (STEMI) in a regional STEMI network: results of the “Herzinfarktverbund Essen.” Herz. March 2008;33(2):136–142. Kramer CM, Rogers WJ, Jr., Mankad S, et al. Contractile reserve and contrast uptake pattern by magnetic resonance imaging and functional recovery after reperfused myocardial infarction. J Am Coll Cardiol. November 15, 2000;36(6):1835–1840. Ingkanisorn WP, Rhoads KL, Aletras AH, et al. Gadolinium delayed enhancement cardiovascular magnetic resonance correlates with clinical measures of myocardial infarction. J Am Coll Cardiol. June 16, 2004;43(12):2253–2259. Dilsizian V. Cardiac magnetic resonance versus SPECT: are all noninfarct myocardial regions created equal? J Nucl Cardiol. January 2007;14(1):9–14. Mahnken AH, Koos R, Katoh M, et al. Assessment of myocardial viability in reperfused acute myocardial infarction using 16-slice computed tomography in comparison to magnetic resonance imaging. J Am Coll Cardiol. June 21, 2005;45(12):2042–2047. Lardo AC, Cordeiro MA, Silva C, et al. Contrast-enhanced multidetector computed tomography viability imaging after myocardial infarction: characterization of myocyte death, microvascular obstruction, and chronic scar. Circulation. January 24, 2006;113(3):394–404. Habis M, Capderou A, Ghostine S, et al. Acute myocardial infarction early viability assessment by 64-slice computed tomography immediately after coronary angiography: comparison with lowdose dobutamine echocardiography. J Am Coll Cardiol. March 20, 2007;49(11):1178–1185. Antman EM, Hand M, Armstrong PW, et al. 2007 focused update of the ACC/AHA 2004 guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College

â•‡ 93. â•‡ 94.

â•‡ 95.

â•‡ 96.

â•‡ 97.

â•‡ 98.

â•‡ 99.

100.

101.

102.

103.

104.

105. 106.

107.

108.

109. 110. 111.

112.

113.

of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. January 15, 2008;51(2):210–247. Min JK, Lin FY, Saba S. Coronary CT angiography: clinical utility and prognosis. Curr Cardiol Rep. January 2009;11(1):47–53. Cheng V, Gutstein A, Wolak A, et al. Moving beyond binary grading of coronary arterial stenoses on coronary computed tomographic angiography: insights for the imager and referring clinician. JACC Cardiovasc Imaging. July 2008;1(4):460–471. Erne P, Schoenenberger AW, Burckhardt D, et al. Effects of percutaneous coronary interventions in silent ischemia after myocardial infarction: the SWISSI II randomized controlled trial. JAMA. May 9, 2007;297(18):1985–1991. Anderson JL, Marshall HW, Bray BE, et al. A randomized trial of intracoronary streptokinase in the treatment of acute myocardial infarction. N Engl J Med. June 2, 1983;308(22):1312–1318. Bestetti A, Lomuscio A, Chiti A, et al. Delayed effect of streptokinase on left ventricular function after acute myocardial infarction assessed by equilibrium gated radionuclide angiocardiography. J Nucl Biol Med. March 1993;37(1):6–11. Stack RS, Phillips HR III, Grierson DS, et al. Functional improvement of jeopardized myocardium following intracoronary streptokinase infusion in acute myocardial infarction. J Clin Invest. July 1983;72(1):84–95. Kloner RA, Allen J, Cox TA, et al. Stunned left ventricular myocardium after exercise treadmill testing in coronary artery disease. Am J Cardiol. August 1, 1991;68(4):329–334. Mathias P, Kerin NZ, Blevins RD, et al. Coronary vasospasm as a cause of stunned myocardium. Am Heart J. February 1987;113 (2, pt 1):383–385. Schneider RM, Weintraub WS, Klein LW, et al. Rate of left ventricular functional recovery by radionuclide angiography after exercise in coronary artery disease. Am J Cardiol. April 15, 1986;57(11):927–932. Wijns W, Serruys PW, Slager CJ, et al. Effect of coronary occlusion during percutaneous transluminal angioplasty in humans on left ventricular chamber stiffness and regional diastolic pressure-radius relations. J Am Coll Cardiol. March 1986;7(3):455–463. DeWood MA, Spores J, Notske R, et al. Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction. N Engl J Med. October 16, 1980;303(16):897–902. Dilsizian V, Cannon RO III, Tracy CM, et al. Enhanced regional left ventricular function after distant coronary bypass by means of improved collateral blood flow. J Am Coll Cardiol. August 1989;14(2):312–318. Levin DC. Pathways and functional significance of the coronary collateral circulation. Circulation. October 1974;50(4):831–837. Rozanski A, Berman D, Gray R, et al. Preoperative prediction of reversible myocardial asynergy by postexercise radionuclide ventriculography. N Engl J Med. July 22, 1982;307(4):212–216. Tillisch J, Brunken R, Marshall R, et al. Reversibility of cardiac wall-motion abnormalities predicted by positron tomography. N Engl J Med. April 3, 1986;314(14):884–888. Matsuzaki M, Gallagher KP, Kemper WS, et al. Sustained regional dysfunction produced by prolonged coronary stenosis: gradual recovery after reperfusion. Circulation. July 1983;68(1):170–182. Rahimtoola SH. Coronary bypass surgery for chronic angina—1981. A perspective. Circulation. February 1982;65(2):225–241. Ross J Jr. Assessment of ischemic regional myocardial dysfunction and its reversibility. Circulation. December 1986;74(6):1186–1190. Schulz R, Guth BD, Pieper K, et al. Recruitment of an inotropic reserve in moderately ischemic myocardium at the expense of metabolic recovery. A model of short-term hibernation. Circ Res. June 1992;70(6):1282–1295. Ellis SG, Wynne J, Braunwald E, et al. Response of reperfusionsalvaged, stunned myocardium to inotropic stimulation. Am Heart J. January 1984;107(1):13–19. Mercier JC, Lando U, Kanmatsuse K, et al. Divergent effects of inotropic stimulation on the ischemic and severely depressed reperfused myocardium. Circulation. August 1982;66(2):397–400.

C HAP T ER 5

•

Post-MI Risk Stratification

114. Smart SC, Sawada S, Ryan T, et al. Low-dose dobutamine echocardiography detects reversible dysfunction after thrombolytic therapy of acute myocardial infarction. Circulation. August 1993; 88(2):405–415. 115. Barilla F, Gheorghiade M, Alam M, et al. Low-dose dobutamine in patients with acute myocardial infarction identifies viable but not contractile myocardium and predicts the magnitude of improvement in wall motion abnormalities in response to coronary revascularization. Am Heart J. December 1991;122(6):1522–1531. 116. Pierard LA, De Landsheere CM, Berthe C, et al. Identification of viable myocardium by echocardiography during dobutamine infusion in patients with myocardial infarction after thrombolytic therapy: comparison with positron emission tomography. J Am Coll Cardiol. April 1990;15(5):1021–1031. 117. Previtali M, Poli A, Lanzarini L, et al. Dobutamine stress echocardiography for assessment of myocardial viability and ischemia in acute myocardial infarction treated with thrombolysis. Am J Cardiol. December 16, 1993;72(19):124G–130G. 118. Hoffer EP, Dewe W, Celentano C, et al. Low-level exercise echocardiography detects contractile reserve and predicts reversible dysfunction after acute myocardial infarction: comparison with low-dose dobutamine echocardiography. J Am Coll Cardiol. October 1999;34(4):989–997. 119. Bigi R, Desideri A, Bax JJ, et al. Prognostic interaction between viability and residual myocardial ischemia by dobutamine stress echocardiography in patients with acute myocardial infarction and mildly impaired left ventricular function. Am J Cardiol. February 1, 2001;87(3):283–288. 120. Nijland F, Kamp O, Verhorst PM, et al. In-hospital and long-term prognostic value of viable myocardium detected by dobutamine echocardiography early after acute myocardial infarction and its relation to indicators of left ventricular systolic dysfunction. Am J Cardiol. November 1, 2001;88(9):949–955. 121. Previtali M, Fetiveau R, Lanzarini L, et al. Prognostic value of myocardial viability and ischemia detected by dobutamine stress echocardiography early after acute myocardial infarction treated with thrombolysis. J Am Coll Cardiol. August 1998;32(2):380–386. 122. Sicari R, Picano E, Landi P, et al. Prognostic value of dobutamineatropine stress echocardiography early after acute myocardial infarction. Echo Dobutamine International Cooperative (EDIC) Study. J Am Coll Cardiol. February 1997;29(2):254–260. 123. Carlos ME, Smart SC, Wynsen JC, et al. Dobutamine stress echocardiography for risk stratification after myocardial infarction. Circulation. March 18, 1997;95(6):1402–1410. 124. Picano E, Sicari R, Landi P, et al. Prognostic value of myocardial viability in medically treated patients with global left ventricular dysfunction early after an acute uncomplicated myocardial infarction: a dobutamine stress echocardiographic study. Circulation. September 15, 1998;98(11):1078–1084. 125. Ragosta M, Camarano G, Kaul S, et al. Microvascular integrity indicates myocellular viability in patients with recent myocardial infarction. New insights using myocardial contrast echocardiography. Circulation. June 1994;89(6):2562–2569. 126. Ito H, Tomooka T, Sakai N, et al. Lack of myocardial perfusion immediately after successful thrombolysis. A predictor of poor recovery of left ventricular function in anterior myocardial infarction. Circulation. May 1992;85(5):1699–1705. 127. Janardhanan R, Swinburn JM, Greaves K, et al. Usefulness of myocardial contrast echocardiography using low-power continuous imaging early after acute myocardial infarction to predict late functional left ventricular recovery. Am J Cardiol. September 1, 2003;92(5):493–497. 128. Jeetley P, Swinburn J, Hickman M, et al. Myocardial contrast echocardiography predicts left ventricular remodelling after acute myocardial infarction. J Am Soc Echocardiogr. October 2004;17(10):1030–1036. 129. Ujino K, Hillis GS, Mulvagh SL, et al. Usefulness of real-time intravenous myocardial contrast echocardiography in predicting left

89

ventricular dilation after successfully reperfused acute myocardial infarction. Am J Cardiol. July 1, 2005;96(1):17–21. 130. Dilsizian V, Rocco TP, Freedman NM, et al. Enhanced detection of ischemic but viable myocardium by the reinjection of thallium after stress-redistribution imaging. N Engl J Med. July 19, 1990;323(3):141–146. 131. Inglese E, Brambilla M, Dondi M, et al. Assessment of myocardial viability after thallium-201 reinjection or rest-redistribution imaging: a multicenter study. The Italian Group of Nuclear Cardiology. J Nucl Med. April 1995;36(4):555–563. 132. Kennedy NS, Cook B, Choy AM, et al. A comparison of the redistribution and reinjection techniques in dipyridamole thallium tomography. Nucl Med Commun. June 1993;14(6):479–484. 133. Kiat H, Berman DS, Maddahi J, et al. Late reversibility of tomographic myocardial thallium-201 defects: an accurate marker of myocardial viability. J Am Coll Cardiol. December 1988;12(6):1456–1463. 134. Lekakis J, Vassilopoulos N, Germanidis J, et al. Detection of Â�viable tissue in healed infarcted myocardium by dipyridamole thallium-201 reinjection and regional wall motion studies. Am J Cardiol. February 15, 1993;71(5):401–404. 135. Dilsizian V, Perrone-Filardi P, Arrighi JA, et al. Concordance and discordance between stress-redistribution-reinjection and restredistribution thallium imaging for assessing viable myocardium. Comparison with metabolic activity by positron emission tomography. Circulation. September 1993;88(3):941–952. 136. Iskandrian AS, Hakki AH, Kane SA, et al. Rest and redistribution thallium-201 myocardial scintigraphy to predict improvement in left ventricular function after coronary arterial bypass grafting. Am J Cardiol. May 1, 1983;51(8):1312–1316. 137. Mori T, Minamiji K, Kurogane H, et al. Rest-injected thallium-201 imaging for assessing viability of severe asynergic regions. J Nucl Med. September 1991;32(9):1718–1724. 138. Ragosta M, Beller GA, Watson DD, et al. Quantitative planar restredistribution 201Tl imaging in detection of myocardial viability and prediction of improvement in left ventricular Â�function after coronary bypass surgery in patients with severely depressed left ventricular function. Circulation. May 1993;87(5):1630–1641. 139. Dilsizian V, Freedman NM, Bacharach SL, et al. Regional thallium uptake in irreversible defects. Magnitude of change in thallium activity after reinjection distinguishes viable from nonviable myocardium. Circulation. February 1992;85(2):627–634. 140. Zimmermann R, Mall G, Rauch B, et al. Residual 201Tl activity in irreversible defects as a marker of myocardial viability. Clinicopathological study. Circulation. February 15, 1995;91(4):1016–1021. 141. Sabia PJ, Powers ER, Ragosta M, et al. Role of quantitative planar thallium-201 imaging for determining viability in patients with acute myocardial infarction and a totally occluded infarct-related artery. J Nucl Med. May 1993;34(5):728–736. 142. Lew AS, Maddahi J, Shah PK, et al. Critically ischemic myocardium in clinically stable patients following thrombolytic therapy for acute myocardial infarction: potential implications for early coronary angioplasty in selected patients. Am Heart J. November 1990;120(5):1015–1025. 143. Lomboy CT, Schulman DS, Grill HP, et al. Rest-redistribution thallium-201 scintigraphy to determine myocardial viability early after myocardial infarction. J Am Coll Cardiol. January 1995;25(1):210–217. 144. Freeman I, Grunwald AM, Hoory S, et al. Effect of coronary occlusion and myocardial viability on myocardial activity of technetium99m-sestamibi. J Nucl Med. February 1991;32(2):292–298. 145. Altehoefer C, Kaiser HJ, Dorr R, et al. Fluorine-18 deoxyglucose PET for assessment of viable myocardium in perfusion defects in 99m Tc-MIBI SPET: a comparative study in patients with coronary artery disease. Eur J Nucl Med. 1992;19(5):334–342. 146. Altehoefer C, vom Dahl J, Biedermann M, et al. Significance of defect severity in technetium-99m-MIBI SPECT at rest to assess myocardial viability: comparison with fluorine-18-FDG PET. J Nucl Med. April 1994;35(4):569–574.

90

147. Arrighi JA, Ng CK, Dey HM, et al. Effect of left ventricular function on the assessment of myocardial viability by technectium-99m sestamibi and correlation with positron emission tomography in patients with healed myocardial infarcts or stable angina pectoris, or both. Am J Cardiol. October 15, 1997;80(8):1007–1013. 148. Bonow RO, Dilsizian V. Thallium-201 and technetium-99msestamibi for assessing viable myocardium. J Nucl Med. May 1992;33(5):815–818. 149. Cuocolo A, Pace L, Ricciardelli B, et al. Identification of viable myocardium in patients with chronic coronary artery disease: comparison of thallium-201 scintigraphy with reinjection and technetium-99m-methoxyisobutyl isonitrile. J Nucl Med. April 1992;33(4):505–511. 150. Dilsizian V, Arrighi JA, Diodati JG, et al. Myocardial viability in patients with chronic coronary artery disease. Comparison of 99m Tc-sestamibi with thallium reinjection and [18F]fluorodeoxyglucose. Circulation. February 1994;89(2):578–587. 151. Marzullo P, Sambuceti G, Parodi O, et al. Regional concordance and discordance between rest thallium 201 and sestamibi imaging for assessing tissue viability: comparison with postrevascularization functional recovery. J Nucl Cardiol. July-August 1995;2(4):309–316. 152. Maurea S, Cuocolo A, Nicolai E, et al. Improved detection of viable myocardium with thallium-201 reinjection in chronic coronary artery disease: comparison with technetium-99m-MIBI imaging. J Nucl Med. April 1994;35(4):621–624. 153. Rocco TP, Dilsizian V, Strauss HW, et al. Technetium-99m isonitrile myocardial uptake at rest. II. Relation to clinical markers of potential viability. J Am Coll Cardiol. December 1989;14(7):1678–1684. 154. Sawada SG, Allman KC, Muzik O, et al. Positron emission tomography detects evidence of viability in rest technetium-99m sestamibi defects. J Am Coll Cardiol. January 1994;23(1):92–98. 155. Soufer R, Dey HM, Ng CK, et al. Comparison of sestamibi singlephoton emission computed tomography with positron emission tomography for estimating left ventricular myocardial viability. Am J Cardiol. June 15, 1995;75(17):1214–1219. 156. Udelson JE, Coleman PS, Metherall J, et al. Predicting recovery of severe regional ventricular dysfunction. Comparison of resting scintigraphy with 201Tl and 99mTc-sestamibi. Circulation. June 1994;89(6):2552–2561. 157. Acampa W, Cuocolo A, Petretta M, et al. Tetrofosmin imaging in the detection of myocardial viability in patients with previous myocardial infarction: comparison with sestamibi and Tl-201 scintigraphy. J Nucl Cardiol. January-February 2002;9(1):33–40. 158. Bisi G, Sciagra R, Santoro GM, et al. Sublingual isosorbide dinitrate to improve technetium-99m-teboroxime perfusion defect reversibility. J Nucl Med. August 1994;35(8):1274–1278. 159. Galli M, Marcassa C, Imparato A, et al. Effects of nitroglycerin by technetium-99m sestamibi tomoscintigraphy on resting regional myocardial hypoperfusion in stable patients with healed myocardial infarction. Am J Cardiol. November 1, 1994;74(9):843–848. 160. Giorgetti A, Marzullo P, Sambuceti G, et al. Baseline/post-nitrate Tc-99m tetrofosmin mismatch for the assessment of myocardial viability in patients with severe left ventricular dysfunction: comparison with baseline Tc-99m tetrofosmin scintigraphy/FDG PET imaging. J Nucl Cardiol. March-April 2004;11(2):142–151. 161. Giorgetti A, Pingitore A, Favilli B, et al. Baseline/postnitrate tetrofosmin SPECT for myocardial viability assessment in patients with postischemic severe left ventricular dysfunction: new evidence from MRI. J Nucl Med. August 2005;46(8):1285–1293. 162. Sciagra R, Leoncini M, Marcucci G, et al. Technetium-99m sestamibi imaging to predict left ventricular ejection fraction outcome after revascularisation in patients with chronic coronary artery disease and left ventricular dysfunction: comparison between baseline and nitrateenhanced imaging. Eur J Nucl Med. June 2001;28(6):680–687. 163. Senior R, Kaul S, Raval U, et al. Impact of revascularization and myocardial viability determined by nitrate-enhanced Tc-99m sestamibi and Tl-201 imaging on mortality and functional outcome in ischemic cardiomyopathy. J Nucl Cardiol. September-October 2002;9(5):454–462.

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164. Levine MG, McGill CC, Ahlberg AW, et al. Functional assessment with electrocardiographic gated single-photon emission computed tomography improves the ability of technetium-99m sestamibi myocardial perfusion imaging to predict myocardial viability in patients undergoing revascularization. Am J Cardiol. January 1, 1999; 83(1):1–5. 165. Leoncini M, Sciagra R, Bellandi F, et al. Low-dose dobutamine nitrate-enhanced technetium 99m sestamibi gated SPECT versus low-dose dobutamine echocardiography for detecting reversible dysfunction in ischemic cardiomyopathy. J Nucl Cardiol. JulyAugust 2002;9(4):402–406. 166. Slart RH, Bax JJ, Sluiter WJ, et al. Added value of attenuation-Â� corrected Tc-99m tetrofosmin SPECT for the detection of myocardial viability: comparison with FDG SPECT. J Nucl Cardiol. November– December 2004;11(6):689–696. 167. Greenfield RA, Swain JL. Disruption of myofibrillar energy use: dual mechanisms that may contribute to postischemic dysfunction in stunned myocardium. Circ Res. February 1987;60(2):283–289. 168. Engler R, Covell JW. Granulocytes cause reperfusion ventricular dysfunction after 15-minute ischemia in the dog. Circ Res. July 1987;61(1):20–28. 169. Ciuffo AA, Ouyang P, Becker LC, et al. Reduction of sympathetic inotropic response after ischemia in dogs. Contributor to stunned myocardium. J Clin Invest. May 1985;75(5):1504–1509. 170. Mochizuki S, Neely JR. Energy metabolism during reperfusion following ischemia. J Physiol (Paris).1980;76(7):805–812. 171. Myears DW, Sobel BE, Bergmann SR. Substrate use in ischemic and reperfused canine myocardium: quantitative considerations. Am J Physiol. July 1987;253(1, pt 2):H107–H114. 172. Marshall RC, Tillisch JH, Phelps ME, et al. Identification and differentiation of resting myocardial ischemia and infarction in man with positron computed tomography, 18F-labeled fluorodeoxyglucose and N-13 ammonia. Circulation. April 1983;67(4):766–778. 173. Schwaiger M, Brunken R, Grover-McKay M, et al. Regional myocardial metabolism in patients with acute myocardial infarction assessed by positron emission tomography. J Am Coll Cardiol. October 1986;8(4):800–808. 174. Schwaiger M, Brunken RC, Krivokapich J, et al. Beneficial effect of residual anterograde flow on tissue viability as assessed by positron emission tomography in patients with myocardial infarction. Eur Heart J. September 1987;8(9):981–988. 175. Dilsizian V, Bateman TM, Bergmann SR, et al. Metabolic imaging with beta-methyl-p-[(123)I]-iodophenyl-pentadecanoic acid identifies ischemic memory after demand ischemia. Circulation. October 4, 2005;112(14):2169–2174. 176. Taegtmeyer H, Dilsizian V. Imaging myocardial metabolism and ischemic memory. Nat Clin Pract Cardiovasc Med. August 2008;5(suppl 2):S42–S48. 177. Miller DD, Gill JB, Livni E, et al. Fatty acid analogue accumulation: a marker of myocyte viability in ischemic-reperfused myocardium. Circ Res. October 1988;63(4):681–692. 178. Tamaki N, Kawamoto M, Yonekura Y, et al. Regional metabolic abnormality in relation to perfusion and wall motion in patients with myocardial infarction: assessment with emission tomography using an iodinated branched fatty acid analog. J Nucl Med. May 1992;33(5):659–667. 179. Kawamoto M, Tamaki N, Yonekura Y, et al. Combined study with I-123 fatty acid and thallium-201 to assess ischemic myocardium: comparison with thallium redistribution and glucose metabolism. Ann Nucl Med. February 1994;8(1):47–54. 180. Myerburg RJ. Sudden cardiac death: exploring the limits of our knowledge. J Cardiovasc Electrophysiol. March 2001;12(3):369–381. 181. Adabag AS, Therneau TM, Gersh BJ, et al. Sudden death after myocardial infarction. JAMA. November 5, 2008;300(17):2022–2029. 182. Solomon SD, Zelenkofske S, McMurray JJ, et al. Sudden death in patients with myocardial infarction and left ventricular dysfunction, heart failure, or both. N Engl J Med. June 23, 2005;352(25):2581–2588.

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183. Zaret BL, Wackers FJ, Terrin ML, et al. Value of radionuclide rest and exercise left ventricular ejection fraction in assessing survival of patients after thrombolytic therapy for acute myocardial infarction: results of thrombolysis in myocardial infarction (TIMI) phase II study. The TIMI Study Group. J Am Coll Cardiol. July 1995;26(1):73–79. 184. Greenberg H, Case RB, Moss AJ, et al. Analysis of mortality events in the multicenter automatic defibrillator implantation trial (MADIT-II). J Am Coll Cardiol. April 21, 2004;43(8):1459–1465. 185. Epstein AE, DiMarco JP, Ellenbogen KA, et al. ACC/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices) developed in collaboration with the American Association for Thoracic Surgery and Society of Thoracic Surgeons. J Am Coll Cardiol. May 27, 2008;51(21):e1–e62. 186. Makikallio TH, Barthel P, Schneider R, et al. Prediction of sudden cardiac death after acute myocardial infarction: role of Holter monitoring in the modern treatment era. Eur Heart J. April 2005;26(8):762–769. 187. Waspe LE, Seinfeld D, Ferrick A, et al. Prediction of sudden death and spontaneous ventricular tachycardia in survivors of complicated myocardial infarction: value of the response to programmed stimulation using a maximum of three ventricular extrastimuli. J Am Coll Cardiol. June 1985;5(6):1292–1301. 188. Paganelli F, Barnay P, Imbert-Joscht I, et al. Influence of residual myocardial ischaemia on induced ventricular arrhythmias following a first acute myocardial infarction. Eur Heart J. October 2001;22(20):1931–1937. 189. Brunckhorst CB, Delacretaz E, Soejima K, et al. Identification of the ventricular tachycardia isthmus after infarction by pace mapping. Circulation. August 10, 2004;110(6):652–659.

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190. Stevenson WG, Friedman PL, Sager PT, et al. Exploring postinfarction reentrant ventricular tachycardia with entrainment mapping. J Am Coll Cardiol. May 1997;29(6):1180–1189. 191. Zipes DP, Wellens HJ. Sudden cardiac death. Circulation. November 24, 1998;98(21):2334–2351. 192. Damle RS, Robinson NS, Ye DZ, et al. Electrical activation during ventricular fibrillation in the subacute and chronic phases of healing canine myocardial infarction. Circulation. August 1, 1995;92(3):535–545. 193. Deneke T, Muller KM, Lemke B, et al. Human histopathology of electroanatomic mapping after cooled-tip radiofrequency ablation to treat ventricular tachycardia in remote myocardial infarction. J Cardiovasc Electrophysiol. November 2005;16(11):1246–1251. 194. Peters NS, Wit AL. Myocardial architecture and ventricular arrhythmogenesis. Circulation. May 5, 1998;97(17):1746–1754. 195. Schmidt A, Azevedo CF, Cheng A, et al. Infarct tissue heterogeneity by magnetic resonance imaging identifies enhanced cardiac arrhythmia susceptibility in patients with left ventricular dysfunction. Circulation. April 17, 2007;115(15):2006–2014. 196. Floras JS. Clinical aspects of sympathetic activation and parasympathetic withdrawal in heart failure. J Am Coll Cardiol. October 1993;22(4)(suppl A):72A–84A. 197. Schwaiger M, Bengel F. Myocardial Innervation. In: V D, J N, eds. Atlas of Nuclear Cardiology. 2nd ed. Philadelphia: Current Medicine; 2006:237–251. 198. Patel AD, Iskandrian AE. MIBG imaging. J Nucl Cardiol. JanuaryFebruary 2002;9(1):75–94. 199. Tamaki S, Yamada T, Okuyama Y, et al. Cardiac iodine-123 metaiodobenzylguanidine imaging predicts sudden cardiac death independently of left ventricular ejection fraction in patients with chronic heart failure and left ventricular systolic dysfunction: results from a comparative study with signal-averaged electrocardiogram, heart rate variability, and QT dispersion. J Am Coll Cardiol. February 3, 2009;53(5):426–435.

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Evaluation After Coronary Revascularization

jo anne D. SCHUij F ErnsT E. va n d er WaLL je r oen j. BaX

Revascularization, by means of either percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG), plays an important role in the treatment of patients with coronary artery disease (CAD). In patients presenting with acute myocardial infarction, primary PCI in combination with stent placement has become the preferred therapeutic option [1]. Randomized clinical trials have shown that as compared to in-hospital fibrinolytic therapy, primary PCI results in more effective restoration of coronary patency while avoiding some of the bleeding risks associated with fibrinolysis [2]. In addition, elective PCI with possible stent placement is increasingly performed in patients presenting with stable CAD and evidence of ischemia. Subanalysis of the serial myocardial perfusion scintigraphy (MPS) studies of the recent clinical outcomes utilizing revascularization and aggressive drug evaluation COURAGE trial showed that the addition of PCI to optimal medical therapy resulted in significantly more effective reduction of ischemia as compared to medical therapy alone [3]. Importantly, this benefit was greatest among patients with more severe ischemia on MPS at baseline. Conversely, evidence is accumulating that the benefits of revascularization are limited when ischemia is absent and in these patients, medical therapy may be preferred [4,5]. Although an increasing number of patients undergo revascularization by means of PCI, CABG remains at present the preferred strategy in patients with complex CAD, including the presence of left main or multivessel disease. Improved outcomes have been demonstrated with CABG as compared to PCI, particularly in patients with underlying diabetes [6]. Despite advances in both revascularization techniques and therapy, restenosis or graft occlusion remains a clinically important problem. After CABG, the likelihood of graft failure is to a large extent dictated by the type of graft used. Patency rates for arterial or internal mammary grafts are 95% at 1 year and 87% after 6 years [7]. In contrast, 92

patency rates for vein grafts are substantially lower with only 84% of grafts being patent after 1 year [7]. This percentage is further reduced to 69% after 6 years. Concerning PCI, the introduction of coronary stents has resulted in significant reduction of restenosis rate [8,9]. Further decline of restenosis rates has been achieved by developments in stent design and coating, including the introduction of drug-eluting stents. Nevertheless, some patients continue to present with in-stent restenosis within 3 to 9 months [8,9]. Importantly, restenosis or graft failure is relatively Â�difficult to recognize as the recurrence of angina or shortness of breath are relatively poor predictors. In addition, exercise electrocardiogram (ECG) has repeatedly been demonstrated to have insufficient accuracy in detecting restenosis following revascularization [9,10]. To accurately identify patients requiring repeat intervention, noninvasive imaging modalities are therefore increasingly used for both diagnostic and prognostic purposes. The purpose of the present chapter is to provide an overview of the different noninvasive imaging modalities that are available to evaluate patients after revascularization.

j â•…F UNCTIONAL IMAGING TECHNIQUES—ASSESSMENT OF MYOCARDIAL ISCHEMIA Traditionally, functional imaging techniques have been used in the initial noninvasive diagnosis of recurrent Â�stenosis. During functional testing, images are acquired during rest and stress conditions. To this end, exercise stress is most commonly performed, but pharmacological stress (using dipyridamole, adenosine, or dobutamine) is also frequently applied. The rationale underlying functional, or stress, imaging techniques is the fact that in the presence of a significant stenosis, the increased demand in blood flow during stress cannot be met. As a result, ischemia occurs, reflected by either perfusion or wall motion abnormalities. Accordingly, although functional imaging techniques do not directly visualize restenosis or graft Â�failure, they provide indirect evidence of the presence of a flow-limiting stenosis.

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Although stress testing in general is also considered to be safe early after PCI, caution is indicated when interpreting its results. Early after PCI, absolute coronary flow can still be diminished due to endothelial dysfunction and injury at the treated site. As a result, regional hypoperfusion can be observed in the absence of a stenosed coronary artery. Due to this high false-positive rate, the role of noninvasive functional imaging to detect restenosis early after PCI (,3 months) may be limited [9]. Thus, in patients presenting with suspected restenosis within 3 months of revascularization, angiographic evaluation may be preferred. Nevertheless, functional testing may still be helpful in patients with known incomplete revascularization to assess the need for additional intervention of lesions untreated during the primary intervention. Several functional imaging techniques are available. While MPS and stress echocardiography are the most commonly used techniques, functional imaging can also be performed with magnetic resonance imaging (MRI). The (potential) value of each of these techniques in the evaluation of patients after revascularization will be discussed in the following paragraphs.

Numerous investigations have also addressed the use of MPS to identify graft stenosis. Lakkis et al performed both exercise MPS (using thallium-201) and coronary angiography in symptomatic patients with previous CABG (51 6 47 months ago) [13]. The authors observed a high sensitivity (83%) for the detection of graft stenosis with accurate allocation of graft stenosis site. More recently, Elhendy et al evaluated 71 predominantly symptomatic patients with limited exercise capacity using dobutamineatropine stress MPS (using thallium-201 or technetium99m sestamibi) [14]. Imaging was performed on average 3.7 6 3.5 years after CABG. In line with previous studies, good diagnostic accuracy (80%) was observed, with a sensitivity and specificity of 81% and 79%, respectively. Interestingly, a tendency toward lower stress heart rates and higher prevalence of single-vessel rather than multivessel disease was noted in patients with false-negative findings. Moreover, higher perfusion scores and numbers of ischemic segments were observed in patients with multivessel stenosis as compared to patients with single-vessel stenosis. An example of a patient with previous CABG and ischemia identified on MPS is provided in Figure 6.1.

Myocardial Perfusion Scintigraphy

Stress Echocardiography

MPS by means of single photon emission computed tomography (SPECT) is one of the most established techniques in the evaluation of ischemia. It is a robust technique that relies on the injection of a radionuclide to visualize myocardial perfusion. As with all functional imaging techniques, MPS allows differentiation between regions showing ischemia (reversible defects) and scar (irreversible defects). While in the past thallium-201 was used to visualize perfusion, technetium-99m labeled agents are currently more frequently used due to the shorter half-life and favorable energy characteristics. In addition, ECG gating has become possible, allowing simultaneous assessment of global and regional function in addition to perfusion. This information has been shown to be incremental for both diagnosis and prognosis, while improving diagnostic certainty as well [11]. A wealth of data are available concerning the diagnostic accuracy of this technique, both in patients with suspected CAD and in patients with previous revascularization. The diagnostic performance of MPS in patients after PCI was recently investigated in a meta-analysis by Giedd and Bergmann [9]. The authors evaluated 6 studies including 640 patients undergoing MPS and coronary angiography late after PCI (2–48 months). Overall, MPS was shown to have a sensitivity and specificity of 79%. Importantly, lower diagnostic accuracies with decreased specificity in particular were reported in patients early (,2 months) after PCI. Similar to the general population, the addition of left ventricular systolic function data has been shown to facilitate detection of in-stent restenosis [12].

An alternative modality to evaluate the presence of ischemia is stress echocardiography. As compared to other functional techniques, echocardiography has the advantage that it is widely available, convenient, associated with low costs, and free of radiation. The occurrence of wall motion abnormalities during exercise or dobutamine stress serve as a marker for restenosis. Moreover, with the recent introduction of ultrasound contrast agents (most often used to improve endocardial border delineation) myocardial perfusion can also be evaluated. The technique has been studied extensively, both in patients with suspected CAD and in those with previous revascularization. In a recent meta-analysis by Scherhag et al, a total of 13 studies with 989 patients were evaluated, all comparing stress echocardiography to invasive coronary angioÂ� graphy at least 3 months after successful PCI [15]. For the detection of significant restenosis after PCI, mean sensitivity and specificity of 74% and 87% were observed with Â�corresponding positive and negative predictive values of 83% and 97%. More recently, the diagnostic value of dobutamine stress myocardial contrast perfusion echocardiography was evaluated in 56 patients with a history of PCI by Elhendy et al [16]. The authors observed a sensitivity of stress echocardiography for the regional diagnosis of restenosis of 73% with a corresponding specificity of 75%. Importantly, on a patient basis, reversible perfusion abnormalities were detected in 93% of patients with restenosis, indicating that the technique may be useful to identify patients with restenosis after PCI.

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F igure 6 . 1 â•…An example of myocardial perfusion scintigraphy during rest and adenosine stress. A 78-year-old male, who had undergone coronary bypass grafting 15 years ago, presented to the outpatient clinic with chest pain. Adenosine stress single photon emission computed tomography myocardial perfusion scintigraphy showed reversible defects in the anterior, lateral, and inferior wall (indicated by arrows), indicating the presence of ischemia. Coronary angiography confirmed occlusion of both vein grafts to the right coronary artery and left circumflex coronary artery. While the arterial graft to the left anterior descending coronary artery was patent, a significant stenosis distal to the anastomosis was observed as well.

Relatively more data are available in patients with Â� previous CABG. Kafka et al compared exercise stress echocardiography to exercise ECG testing in 182 patients with a history of CABG [17]. Inconclusive tests were more Â�frequently obtained for exercise ECG (28%) than exercise echocardiography (9%). In addition, diagnostic performance of exercise echocardiography was clearly superior. While positive and negative predictive values for significant graft or native coronary artery disease were, respectively, 62% and 52% for stress ECG, significantly higher values were observed for stress echocardiography (85% and 81%, respectively). Interestingly, in line with data obtained in patients without CABG, sensitivity tended to be higher for the detection of multivessel disease as compared to singlevessel restenosis. Similar findings were reported by Elhendy et al, who evaluated the diagnostic accuracy of dobutamine stress echocardiography to detect graft disease in 50 patients unable to exercise [18]. Overall, a sensitivity and specificity of, respectively, 78% and 89% were obtained, while in this study sensitivity also increased when restenosis occurred in more than one vascular territory. Recently, dobutamine stress echocardiography has also been applied in combination with contrast agents to assess myocardial perfusion in patients with previous CABG [19]. In 62 patients, myocardial perfusion was evaluated during rest and dobutamine-atropine stress. Perfusion abnormalities were identified in 49 of 54 patients with significant Â�disease (native ungrafted artery and/or graft disease), resulting in a sensitivity

of 90%. Due to the high prevalence of disease, a somewhat lower specificity of 70% was observed. Nevertheless, overall diagnostic accuracy was 88%, indicating the potential of dobutamine stress myocardial perfusion echocardiography to evaluate graft disease. An example is provided in Figure 6.2. Magnetic Resonance Imaging MRI offers the advantage of high spatial resolution without the use of radiation. Relatively few studies are available that have addressed the use of this technique in the diagnosis of restenosis following revascularization. With MRI, the presence of myocardial ischemia resulting from recurrent stenosis can be evaluated using either perfusion or wall motion imaging. To evaluate myocardial perfusion, short-axis slices are acquired during the first pass of a bolus of gadolinium. Consequently, areas with reduced perfusion are identified as regions with lower signal intensity. Similarly, the induction of wall motion abnormalities during stress can be evaluated and also serves as a sign of ischemia (Figure 6.3). Since physical exercise is difficult in the magnetic bore, pharmacological stressors are usually applied. Thus far, the majority of data on perfusion or wall motion MRI have been obtained in patients without previous revascularization. Doesch et al recently evaluated a heterogeneous population of 141 patients scheduled for invasive coronary angiography with adenosine stress perfusion MRI [20]. Importantly, subanalysis of the patients with prior revascularization revealed

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Figure 6.2â•…An example of myocardial contrast echocardiography during rest and dobutamine stress. Myocardial contrast echocardiographic (MCE) images from apical 2-chamber view at rest (top right) and peak dobutamine stress (top left) of a 73-year-old woman who presented with exertional dyspnea 3 years after coronary artery bypass grafting. A reversible perfusion abnormality can be observed in the inferior wall (arrows). Subsequent angiography (angio) demonstrated an occluded right coronary artery (RCA) (bottom right) and severe proximal stenosis of related saphenous vein graft (SVG) (bottom left). Reprinted with permission from Ref. 19.

F igure 6 . 3 â•…An example of high-dose dobutamine-atropine stress magnetic resonance imaging. Apical short-axis magnetic resonance images obtained at rest and at low-dose and peak-dose dobutamine stress. Both end-diastolic (ED) and end-systolic (ES) phases are shown. Note the development of inferior akinesia (arrow) at peak dobutamine stress. Invasive coronary angiography confirmed the presence of significant stenosis in the left circumflex coronary artery and right coronary artery. Reprinted with permission from Ref. 21.

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comparable diagnostic performance as compared to patients without a history of revascularization. In 88 patients with previous PCI, sensitivity and specificity were 92% and 75%, respectively, with an overall diagnostic accuracy of 84%. Similar sensitivity (88%) but somewhat lower specificity (67%) were observed in patients with previous CABG (n 5 21), resulting in an overall diagnostic performance of 85%. Comparable findings were reported by Wahl et al [21]. The authors performed high-dose dobutamine-atropine stress MRI in 160 patients with a history of revascularization and wall motion abnormalities at rest, a population in which detection of ischemia with stress echocardiography is frequently difficult. Observed sensitivity and specificity for detection of significant CAD were, respectively, 89% and 84% with an overall diagnostic accuracy of 88%, supporting the potential usefulness of this modality in the follow-up of patients after revascularization. Nevertheless, although MRI offers clear advantages over other techniques, including higher spatial resolution and the lack of radiation, widespread use of MRI is still limited for several reasons. First, the use of a magnetic field precludes evaluation of patients with intracranial clips, pacemakers, or defibrillators, while claustrophobia is another exclusion criterion. Finally, a high level of experience is required for both data acquisition and analysis.

j â•…A NATOMICAL IMAGING TECHNIQUES— ASSESSMENT OF RESTENOSIS In addition to functional imaging techniques, modalities that allow noninvasive anatomical imaging have been developed. Initial investigations on direct noninvasive

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visualization of recurrent coronary or graft disease following revascularization employed electron beam computed tomography (EBCT) technology [22–24], while more recently the feasibility of MRI to noninvasively assess coronary and graft integrity has been shown as well. However, with the introduction of Multidetector row computed tomography (MDCT), the focus has shifted to the use of this technique for noninvasive coronary angiography. In the following paragraphs, the potential value of both MDCT and MRI in patients after revascularization will be discussed. Multidetector Row Computed Tomography Angiography MDCT coronary angiography is a rapidly developing technique that is increasingly used in the evaluation of patients with suspected CAD. While the feasibility of noninvasive coronary angiography with MDCT was shown with 4-slice systems, currently 64-slice and even 320-row systems are available. During the administration of a bolus of contrast agent, a 3D data set of the entire heart is obtained within a single breath hold. Data acquisition is performed during ECG gating to allow reconstruction of motion-free images. In line with single-center studies, a recent multicenter trial in 230 patients showed a sensitivity and specificity of 95% and 83%, respectively [25]. Importantly, consistently high negative predictive values (approaching 100%) have been observed and therefore the technique is particularly promoted in patients with low-to-intermediate pretest likelihood to rule out significant CAD with high diagnostic certainty [26]. In contrast, clinical utility of the technique in patients with established CAD may be restricted to selected cases [26]. Examples of MDCT angiography in patients after revascularization are provided in Figures 6.4 and 6.5.

Figure 6.4â•…An example of multidetector row computed tomography angiography poststent placement. In panel A (conventional coronary angiogram), the presence of a high-grade in-stent restenosis in the proximal part of a stent placed in the left anterior descending coronary artery can be observed as indicated by the arrowhead. Also on 64-slice multidetector row computed tomography (panel B), the presence of this high-grade lesion was identified. Note the presence of a large obstructing hypodense lesion in the proximal part of the stent (indicated by the arrowhead). Reprinted with permission from Ref. 29.

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Figure 6.5â•…An example of multidetector row computed tomography

angiography after coronary artery bypass Â�grafting. An 82-year-old male patient with previous coronary bypass grafting (vein graft to the diagonal and left anterior descending coronary artery [LAD]) underwent Â�320-row multidetector row computed tomography. Panel A: 3-dimensional volume-rendered reconstruction; Panel B: enlargement of panel A; Panel C: curved multiplanar reconstruction of the native left anterior descending coronary artery; Panel D: curved multiplanar reconstruction of the vein graft. On the multidetector row computed tomography images, patency of the vein graft as well as severe atherosclerosis (white arrows) in the proximal native LAD can be observed. Note the anastomosis with the diagonal (black arrow) and LAD (white arrowhead).

Diagnostic accuracy studies employing MDCT in patients with previous PCI have focused on the evaluation of coronary stents. Due to their metal content, coronary stents give rise to artifacts in MDCT imaging. Particularly with older generation scanners, the stent lumen was frequently obscured, and evaluation of stent patency depended on the presence of distal runoff. However, this is not an accurate criterion for patency as distal runoff can be due to collateral filling rather than stent patency. Several factors have been identified with a major influence on image quality and diagnostic accuracy. Using 16-slice MDCT, Schuijf et al

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reported that stents with a diameter #3.0 mm were more often uninterpretable as compared to stents with a larger diameter [27]. In addition, a pronounced effect of strut thickness was observed with lower image quality in stents with struts $140 μm. Similar findings were reported in a larger study by Gilard et al, who reported sufficient image quality in only 51% of stents with a diameter of #3.0 mm versus 81% of stents with a diameter .3.0 mm [28]. While overall improved image quality and diagnostic accuracies have been reported using 64-slice technology, results remain highly variable and dependent on stent type, diameter, and configuration. Including only patients with larger stents, Cademartiri et al observed a high sensitivity (95%) and specificity (93%) as well as a low percentage of uninterpretable stents (7%) in 182 patients with 192 stents [29]. Similar findings were recently reported by Sun and Almutairi, who performed a meta-analysis of 14 studies reporting on the diagnostic accuracy of MDCT to detect in-stent restenosis in a total of 1398 stents [30]. Pooled estimates of the sensitivity and specificity of overall 64-slice MDCT angiography for the detection of in-stent restenosis were 90% and 91%, respectively, while stent diameter was shown to be the main factor affecting image quality and diagnostic performance. Moreover, inclusion of the 11% uninterpretable stents resulted in significantly decreased sensitivity (79%) and specificity (81%). Accordingly, while MDCT may be considered for noninvasive exclusion of in-stent restenosis in selected cases with larger stents, use of this technique in the general population after stenting remains limited. As compared to native coronary arteries, coronary bypass grafts are less affected by motion during the cardiac cycle and, in combination with their larger diameter, are relatively easier to visualize with MDCT. Indeed, in several studies excellent results have been reported for the detection of graft occlusion with diagnostic accuracies approaching 100%. Hamon et al recently performed a meta-analysis including 15 investigations using either 16-slice or 64-slice MDCT in patients with previous CABG [31]. Graft assessability ranged from 78% to 100% among studies, resulting in an average of 92%. In the 2023 grafts studied, average sensitivity to detect .50% graft stenosis was shown to be 96% with a corresponding specificity of 97%. Notably, also high positive (93%) and negative (99%) predictive values were reported, further illustrating the potential of MDCT as a noninvasive modality to evaluate graft dysfunction. From a clinical point of view, however, it is important to recognize that recurrent symptoms may arise not only from graft stenosis but also from progression of the disease in nongrafted vessels or in segments distal to the anastomosis. Evaluation by means of MDCT may be hampered due to the frequent occurrence of extensive calcifications in combination with small vessel diameter due to longstanding CAD. Indeed, studies also addressing disease of the native coronary arteries in addition to graft stenosis revealed substantially lower diagnostic accuracies [26]. Accordingly, management

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following noninvasive angiography may still be uncertain in a large proportion of patients post-CABG and referral for functional assessment may still be required to determine the need for repeat intervention and corresponding therapeutic strategy. Nevertheless, selected patients, such as patients with failed graft visualization during invasive coronary angiography, may benefit from MDCT coronary angiography. Magnetic Resonance Imaging In patients with previous revascularization, MRI has mainly been investigated in the setting of previous CABG thus far. In contrast, the in-stent lumen in general cannot be evaluated with MRI due to susceptibility artifacts and radiofrequency shielding, which result in a local signal void. Although the metallic clips used during graft surgery may also result in signal void, this phenomenon occurs to a lesser extent. To evaluate graft disease, MRI offers 2 distinct approaches, namely anatomical assessment of graft integrity by means of magnetic resonance (MR) angiography (as shown in Figure 6.6) and assessment of graft function by means of flow velocity measurements.

Magnetic Resonance Angiography Similar to MDCT, grafts are easier to visualize during MRI as compared to native coronary arteries due to their larger diameter and limited motion during the cardiac cycle. Initial investigations employed 2D spin-echo and gradient-echo techniques to acquire successive axial slices during repetitive breath holds. As compared to invasive coronary angiography,

Multimodality Imaging in Cardiovascular Medicine

sensitivities and specificities ranging from, respectively, 71% to 100% and from 89% to 100% were obtained in the evaluation of graft patency [32–35]. However, degraded image quality was frequently Â�encountered due to low Â�signal-to-noise ratio and low spatial resolution. Substantial improvement in spatial resolution, image quality, and overall procedural success was achieved by the introduction of 3D navigator and contrast-enhanced techniques. Among others, Bunce et al evaluated 34 patients with a total of 79 grafts using gadolinium-enhanced 3D MR angiography and reported a sensitivity and specificity of 73% and 85%, respectively, in the evaluation of graft patency [36]. However, only few investigations attempted to address the diagnostic performance of MR angiography to evaluate graft stenosis rather than patency/occlusion. More detailed grading of the severity of graft stenosis was attempted by Langerak et al [37]. In total, 56 vein grafts from 38 patients with recurrent symptoms were evaluated by MR angiography and invasive coronary angiography. While diagnostic accuracy was high for the evaluation of graft occlusion (sensitivity 83%, specificity 100%), only slightly lower values were observed for the detection of graft stenosis $50% (sensitivity 82%, specificity 88%) and graft stenosis $70% (sensitivity 73%, specificity 80%). Nevertheless, a major limitation of MR angiography remains the fact that similar to MDCT angiography, assessment of the native coronary arteries is frequently difficult while no information on the presence of ischemia is obtained. A potential solution may lie in the combination of MR angiography with functional measurements through MR flow mapping.

F igure 6 . 6 â•…An example of magnetic resonance angiography. Magnetic resonance angiogram and corresponding coronary angiogram (A, 48°

left-anterior-oblique view) of a normal vein graft to the obtuse marginal branch of the left circumflex coronary artery. B1–7, Selection of individual slices of the magnetic resonance angiogram in the oblique coronal plane. Multiplanar reconstruction shows patency of the graft in a single plane (C). Ao, ascending aorta; LV, left ventricle; PA, pulmonary artery. Reprinted with permission from Ref. 37.

CHA P TER 6

•

Evaluation After Coronary Revascularization

Magnetic Resonance Flow Velocity Measurements

99

Numerous investigations have demonstrated the value of noninvasive functional imaging techniques in risk stratification. Indeed, a large body of evidence obtained in the general population indicates a substantially higher risk for coronary events in the presence of ischemia versus a low risk in the absence of any inducible wall motion or perfusion abnormalities. These observations have been confirmed in patients with previous revascularization. In contrast, noninvasive anatomical imaging is a relatively new technique. As a result, only few studies are available addressing its potential prognostic value and no dedicated data are available in patients after revascularization.

et al using exercise technetium-99m sestamibi SPECT [42]. Regardless of symptomatic status, higher event rates were observed in patients with evidence of ischemia on SPECT. Patients after coronary stenting were evaluated by Cottin et al using stress thallium-201, 5 months after stent placement [43]. In total, 152 patients were followed up for an average of 40 6 13 months. Major cardiac events occurred in 3% of patients without ischemia on Â�thallium-201 versus 28% in ischemic patients, resulting in a relative risk of cardiac events of 6.5 for patients with significant ischemia as compared to those without. A heterogeneous population including both patients after CABG (n 5 201) and PCI (n 5 180) was studied by Elhendy et al [44]. During a follow-up period of 3.5 6 1.4 years after exercise or dobutamine stress technetium-99m tetrofosmin SPECT, no hard cardiac events occurred in the 100 patients with normal perfusion. In contrast, 19% of patients with ischemia at baseline imaging experienced a hard event. Importantly, no difference in hard event rates was observed between patients with and without angina before stress testing further underlining the limited value of symptoms in this population. Finally, the issue pertaining to the appropriate timing of evaluation of patients after CABG was addressed by Zellweger et al [45]. From a large clinical database, the authors identified 1544 patients who had undergone MPS (rest thallium-201/stress technetium-99m sestamibi MPS) 7.1 6 5.0 years postCABG. These patients were followed up for at least 1 year after imaging. The authors showed that MPS in patients post-CABG was strongly predictive of cardiac death and provided incremental value over clinical and treadmill test information. When stratifying resulting according to early (#5 years) and late (.5 years) after CABG and symptomatic status, as shown in Figure 6.7, the authors observed that the event rates were low in asymptomatic patients #5 years post-CABG without evident benefit from routine nuclear testing. In symptomatic patients early after CABG, however, the extent and severity of ischemia on nuclear testing was able to stratify patients and guide therapy. This phenomenon was also noted for patients .5 years post-CABG irrespective of symptoms.

Myocardial Perfusion Scintigraphy

Stress Echocardiography

The majority of data have been obtained with nuclear imaging techniques. Lauer et al evaluated the Â�potential prognostic information of exercise and thallium-Â�perfusion variables during 3 years of follow-up in 873 asymptomatic patients with previous CABG who underwent symptomlimited exercise thallium-201 SPECT [41]. Correction for baseline clinical variables revealed that the presence of thallium-perfusion defect was a strong predictor of death (adjusted relative risk 2.78) and major events (adjusted relative risk 2.63) similar to impaired exercise Â�capability. Similar findings were reported by Acampa

In addition to nuclear imaging, the prognostic value of stress echocardiography after revascularization has been studied as well. The predictive power of exercise echocardiography was evaluated by Arruda et al in 718 patients post-CABG [46] during a mean follow-up period of 2.9 years. Compared with clinical, rest echocardiographic, and exercise ECG variables, exercise echocardiography provided significant incremental value for predicting Â�cardiac death and cardiac events (Figure 6.8). In particular, exercise ejection fraction was shown to be an independent predictor of events. In addition, Â�abnormal left ventricular end-systolic volume

With MR flow velocity measurements or flow mapping, the hemodynamical consequences of graft stenosis may be assessed. To this end, blood flow through the graft is measured in rest and during pharmacologically induced stress (adenosine or dipyridamole). Subsequently, the coronary flow reserve (CFR) can be obtained by dividing the flow value during stress by its value in rest. Although technically challenging, promising results have been obtained, particularly with the use of dedicated novel acquisition sequences. In several investigations, good correlations in measurements of peak velocity and velocity reserve were demonstrated between MRI and Doppler flow measurements [38]. Langerak et al performed MRI flow mapping during rest and stress in 69 patients scheduled for invasive coronary angiography due to recurrent chest pain [39]. Based on receiver-operator characteristic curve analysis, the authors showed a sensitivity and specificity of MRI to detect single vein graft stenosis $70% of 96% and 92%, respectively. However, imaging was successful in only 80% of grafts, while even lower values have been reported by other groups [40]. In addition to procedural difficulties, analysis of MRI data remains at present highly time consuming, thereby restricting Â�clinical use.

jâ•…P ROGNOSTIC VALUE OF NONI NVASIVE IMAGING

Multimodality Imaging in Cardiovascular Medicine

3

CABG <5 years

3.1

CABG >5 years

2.5 2.1 2 1.5 1

1

0.7

0.7

0.5 0

0 Normal

Mildly abnormal

Moderately/Severely abnormal

Chi-square

80 60

Clinical + rest Echo Clinical + rest Echo + excercise ECG Clinical + rest Echo + excercise ECG + excercise Echo 0.005 0.02 0.09

0.02 0.03 0.01

40

Ischemia p = 0.0001

1

2

4

3

5

6

7

6

7

6

7

Years No ischemia

100 90 80 70 60 50 40 30

Ischemia p = 0.0002

0

1

2

3

4

5

Years

Probability of survival (%)

C

No ischemia

0

B

F igure 6 . 7 â•…Annual cardiac death rates as a function of the extent of ischemia on myocardial perfusion scintigraphy (MPS) in 1544 patients #5 and .5 years after coronary artery bypass grafting (CABG). Adapted with permission from Ref. 45.

100

100 90 80 70 60 50 40 30

A Probability of survival (%)

Annual cardiac death rate (%)

3.5

Probability of survival (%)

10 0

No ischemia

100 90 80 70 60 50 40 30

Ischemia p = 0.0001

0

1

2

4

3

5

Years

F igure 6 . 9 â•…The prognostic value of dobutamine stress echocardiog-

raphy in 393 patients without typical angina pectoris after coronary revascularization. Kaplan-Meier survival curves are provided for all-cause death (A), cardiac death (B), and hard cardiac events (C) in patients with and without ischemia on stress echocardiography. Reprinted with permission from Ref. 47.

20 0

jâ•… CON CLUSION Cardiac death or MI

Cardiac death

F igure 6 . 8 â•…Incremental value of exercise electrocardioÂ�graphy (ECG)

and exercise echocardiography (Echo) in predicting cardiac events (left) and cardiac death (right). The addition of exercise electrocardiographic variables to the clinical and rest echocardiographic models significantly improved the model for cardiac death. The addition of the exercise echocardiographic variables improved both models. MI, myocardial infarction. Reprinted with permission from Ref. 46.

response to exercise was an independent predictor of cardiac events, while workload was an independent predictor of cardiac death. The prognostic significance of dobutamine stress Â�echocardiography in patients with previous revascularization (previous CABG n 5 186, previous PCI n 5 178, both n 5 29) was tested by Pedone et al [47]. In line with previous studies, the authors showed that the presence of stress-induced ischemia was a strong predictor of both allcause death (hazard ratio 3.5) and cardiac death Â�(hazard ratio 4.2), independent of other clinical data (Figure 6.9).

Despite substantial improvement in revascularization strategies, restenosis remains a clinical problem and still occurs in a substantial proportion of patients after initially successful revascularization. However, diagnosing restenosis is particularly challenging as recurrence of symptoms like angina and shortness of breath have been shown to be relatively poor predictors. In addition, exercise ECG testing also lacks sufficient accuracy in this population. On the other hand, routine invasive coronary angiography cannot be recommended due to the corresponding risk of complications. Not surprisingly therefore, clinicians are increasingly using noninvasive imaging modalities in the management of patients post-revascularization. In patients with suspected restenosis, functional imaging modalities, such as stress echocardiography and MPS, are at present most frequently used. Importantly, the information on the presence and extent of ischemia that is obtained by these techniques has also been shown to be a strong predictor of adverse events, regardless of the symptomatic status. More recently, anatomical imaging approaches have also become available. Promising

CHA P TER 6

•

Evaluation After Coronary Revascularization

results have been obtained with both MDCT and MRI in the evaluation of patients after CABG. In addition, MDCT may allow noninvasive evaluation of patients after PCI, although evaluation remains at present restricted to patients with relatively large diameter stents. As both MDCT and MRI are still under development, their use in the daily clinical management of patients after revascularization is currently limited. Moreover, their potential prognostic value remains to be determined in future studies as well.

jâ•… REFERENCES â•‡â•‡ 1. Van de Werf F, Bax JJ, Betriu A, et al. Management of acute myocardial infarction in patients presenting with persistent ST-segment elevation: the Task Force on the Management of ST-Segment Elevation Acute Myocardial Infarction of the European Society of Cardiology. Eur Heart J. 2008;29(23):2909–2945. â•‡â•‡ 2. Keeley EC, Boura JA, Grines CL. Primary angioplasty Â�versus intravenous thrombolytic therapy for acute myocardial Â�infarction: a quantitative review of 23 randomised trials. Lancet. 2003;361 (9351):13–20. â•‡â•‡ 3. Shaw LJ, Berman DS, Maron DJ, et al. Optimal medical therapy with or without percutaneous coronary intervention to reduce ischemic burden: results from the clinical outcomes utilizing revascularization and aggressive drug evaluation (COURAGE) trial nuclear substudy. Circulation. 2008;117(10):1283–1291. â•‡â•‡ 4. Hachamovitch R, Hayes SW, Friedman JD, Cohen I, Berman DS. Comparison of the short-term survival benefit associated with revascularization compared with medical therapy in patients with no prior coronary artery disease undergoing stress myocardial perfusion single photon emission computed tomography. Circulation. 2003;107(23):2900–2907. â•‡â•‡ 5. Tonino PA, De Bruyne B, Pijls NH, et al. Fractional flow reserve Â�versus angiography for guiding percutaneous coronary intervention. N Engl J Med. 2009;360(3):213–224. â•‡â•‡ 6. Javaid A, Steinberg DH, Buch AN, et al. Outcomes of coronary artery bypass grafting versus percutaneous coronary intervention with drug-eluting stents for patients with multivessel coronary artery disease. Circulation. 2007;116(11)(suppl):I200–I206. â•‡â•‡ 7. Goldman S, Zadina K, Moritz T, et al. Long-term patency of saphenous vein and left internal mammary artery grafts after coronary artery bypass surgery: results from a Department of Veterans Affairs Cooperative Study. J Am Coll Cardiol. 2004;44(11):2149–2156. â•‡â•‡ 8. Anderson HV, Shaw RE, Brindis RG, et al. A contemporary overview of percutaneous coronary interventions: the American College of Cardiology-National Cardiovascular Data Registry (ACC-NCDR). J Am Coll Cardiol. 2002;39(7):1096–1103. â•‡â•‡ 9. Giedd KN, Bergmann SR. Myocardial perfusion imaging following percutaneous coronary intervention: the importance of restenosis, disease progression, and directed reintervention. J Am Coll Cardiol. 2004;43(3):328–336. â•‡ 10. Legrand V, Raskinet B, Laarman G, Danchin N, Morel MA, Serruys PW. Diagnostic value of exercise electrocardiography and angina after coronary artery stenting. Benestent Study Group. Am Heart J. 1997;133(2):240–248. â•‡ 11. Smanio PE, Watson DD, Segalla DL, Vinson EL, Smith WH, Beller GA. Value of gating of technetium-99m sestamibi single-photon Â�emission computed tomographic imaging. J Am Coll Cardiol. 1997; 30(7):1687–1692. â•‡ 12. Cingi E, Temiz NH, Yildirim N, Timurkaynak T, Cengel A, Unlu M. Detection of stent restenosis in single vessel CAD: comparison of 201Tl and gated 99mTc-MIBI SPECT. Nucl Med Commun. 2004;25(5):479–486.

101

â•‡ 13. Lakkis NM, Mahmarian JJ, Verani MS. Exercise thallium-201 single photon emission computed tomography for evaluation of coronary artery bypass graft patency. Am J Cardiol. 1995;76(3):107–111. â•‡ 14. Elhendy A, Van Domburg RT, Bax JJ, et al. Dobutamine-atropine stress myocardial perfusion SPECT imaging in the diagnosis of graft stenosis after coronary artery bypass grafting. J Nucl Cardiol. 1998;5(5):491–497. â•‡ 15. Scherhag A, Pfleger S, Haase KK, Sueselbeck T, Borggrefe M. Diagnostic value of stress echocardiography for the detection of restenosis after PTCA. Int J Cardiol. 2005;98(2):191–197. â•‡ 16. Elhendy A, Tsutsui JM, O’Leary EL, Xie F, Majeed F, Porter TR. Evaluation of restenosis and extent of coronary artery disease in patients with previous percutaneous coronary interventions by dobutamine stress real-time myocardial contrast perfusion imaging. Heart. 2006;92(10):1480–1483. â•‡ 17. Kafka H, Leach AJ, Fitzgibbon GM. Exercise echocardiography after coronary artery bypass surgery: correlation with coronary angiography. J Am Coll Cardiol. 1995;25(5):1019–1023. â•‡ 18. Elhendy A, Geleijnse ML, Roelandt JR, et al. Assessment of patients after coronary artery bypass grafting by dobutamine stress echocardiography. Am J Cardiol. 1996;77(14):1234–1236. â•‡ 19. Elhendy A, Tsutsui JM, O’Leary EL, Xie F, Porter TR. Noninvasive diagnosis of coronary artery bypass graft disease by dobutamine stress real-time myocardial contrast perfusion imaging. J Am Soc Echocardiogr. 2006;19(12):1482–1487. â•‡ 20. Doesch C, Seeger A, Hoevelborn T, et al. Adenosine stress cardiac magnetic resonance imaging for the assessment of ischemic heart disease. Clin Res Cardiol. 2008. â•‡ 21. Wahl A, Paetsch I, Roethemeyer S, Klein C, Fleck E, Nagel E. Highdose dobutamine-atropine stress cardiovascular MR imaging after coronary revascularization in patients with wall motion abnormalities at rest. Radiology. 2004;233(1):210–216. â•‡ 22. Moncada R, Salinas M, Churchill R, et al. Patency of saphenous aortocoronary-bypass grafts demonstrated by computed tomography. N Engl J Med. 1980;303(9):503–505. â•‡ 23. Achenbach S, Moshage W, Ropers D, Nossen J, Bachmann K. Noninvasive, three-dimensional visualization of coronary artery bypass grafts by electron beam tomography. Am J Cardiol. 1997;79(7):856–861. â•‡ 24. Budoff MJ, Achenbach S, Duerinckx A. Clinical utility of computed tomography and magnetic resonance techniques for noninvasive coronary angiography. J Am Coll Cardiol. 2003;42(11):1867–1878. â•‡ 25. Budoff MJ, Dowe D, Jollis JG, et al. Diagnostic performance of 64-multidetector row coronary computed tomographic angiography for evaluation of coronary artery stenosis in individuals without known coronary artery disease: results from the prospective multicenter ACCURACY (Assessment by Coronary Computed Tomographic Angiography of Individuals Undergoing Invasive Coronary Angiography) trial. J Am Coll Cardiol. 2008;52(21):1724–1732. â•‡ 26. Schroeder S, Achenbach S, Bengel F, et al. Cardiac computed tomoÂ� graphy: indications, applications, limitations, and training requirements: report of a Writing Group deployed by the Working Group Nuclear Cardiology and Cardiac CT of the European Society of Cardiology and the European Council of Nuclear Cardiology. Eur Heart J. 2008;29(4):531–556. â•‡ 27. Schuijf JD, Bax JJ, Jukema JW, et al. Feasibility of assessment of coronary stent patency using 16-slice computed tomography. Am J Cardiol. 2004;94(4):427–430. â•‡ 28. Gilard M, Cornily JC, Pennec PY, et al. Assessment of coronary artery stents by 16-slice computed tomography. Heart. 2006;92(1):58–61. â•‡ 29. Cademartiri F, Schuijf JD, Pugliese F, et al. Usefulness of 64-slice multi-slice computed tomography coronary angiography to assess in-stent restenosis. J Am Coll Cardiol. 2007;49(22):2204–2210. â•‡ 30. Sun Z, Almutairi AM. Diagnostic accuracy of 64 multislice CT angiography in the assessment of coronary in-stent restenosis: a meta-analysis. Eur J Radiol. 2010;73(2):266–273. â•‡ 31. Hamon M, Lepage O, Malagutti P, et al. Diagnostic performance of 16- and 64-section spiral CT for coronary artery bypass graft assessment: meta-analysis. Radiology. 2008;247(3):679–686.

10 2

â•‡ 32. Aurigemma GP, Reichek N, Axel L, Schiebler M, Harris C, Kressel HY. Noninvasive determination of coronary artery bypass graft patency by cine magnetic resonance imaging. Circulation. 1989;80(6):1595–1602. â•‡ 33. Frija G, Schouman-Claeys E, Lacombe P, Bismuth V, Ollivier JP. A study of coronary artery bypass graft patency using MR Â�imaging. J Comput Assist Tomogr. 1989;13(2):226–232. â•‡ 34. Galjee MA, van Rossum AC, Doesburg T, van Eenige MJ, Visser CA. Value of magnetic resonance imaging in assessing patency and function of coronary artery bypass grafts. An angiographically controlled study. Circulation. 1996;93(4):660–666. â•‡ 35. Rubinstein RI, Askenase AD, Thickman D, Feldman MS, Agarwal JB, Helfant RH. Magnetic resonance imaging to evaluate patency of aortocoronary bypass grafts. Circulation. 1987;76(4):786–791. â•‡ 36. Bunce NH, Lorenz CH, John AS, Lesser JR, Mohiaddin RH, Pennell DJ. Coronary artery bypass graft patency: assessment with true fast imaging with steady-state precession versus gadoliniumenhanced MR angiography. Radiology. 2003;227(2):440–446. â•‡ 37. Langerak SE, Vliegen HW, de Roos A, et al. Detection of vein graft disease using high-resolution magnetic resonance angiography. Circulation. 2002;105(3):328–333. â•‡ 38. Langerak SE, Kunz P, Vliegen HW, et al. MR flow mapping in coronary artery bypass grafts: a validation study with Doppler flow measurements. Radiology. 2002;222(1):127–135. â•‡ 39. Langerak SE, Vliegen HW, Jukema JW et al. Value of magnetic resonance imaging for the noninvasive detection of stenosis in coronary artery bypass grafts and recipient coronary arteries. Circulation. 2003;107(11):1502–1508. â•‡ 40. Brenner P, Wintersperger B, von Smekal A, et al. Detection of coronary artery bypass graft patency by contrast enhanced magnetic resonance angiography. Eur J Cardiothorac Surg. 1999;15(4):389–393.

Multimodality Imaging in Cardiovascular Medicine

â•‡ 41. Lauer MS, Lytle B, Pashkow F, Snader CE, Marwick TH. Prediction of death and myocardial infarction by screening with exercisethallium testing after coronary-artery-bypass grafting. Lancet. 1998;351(9103):615–622. â•‡ 42. Acampa W, Petretta M, Florimonte L, Mattera A, Cuocolo A. Prognostic value of exercise cardiac tomography performed late after percutaneous coronary intervention in symptomatic and symptom-free patients. Am J Cardiol. 2003;91(3):259–263. â•‡ 43. Cottin Y, Rezaizadeh K, Touzery C, et al. Long-term prognostic value of 201Tl single-photon emission computed tomographic myocardial perfusion imaging after coronary stenting. Am Heart J. 2001;141(6):999–1006. â•‡ 44. Elhendy A, Schinkel AF, Van Domburg RT, Bax JJ, Valkema R, Poldermans D. Risk stratification of patients after myocardial revascularization by stress Tc-99m tetrofosmin myocardial perfusion tomography. J Nucl Cardiol. 2003;10(6):615–622. â•‡ 45. Zellweger MJ, Lewin HC, Lai S, et al. When to stress patients after coronary artery bypass surgery? Risk stratification in patients early and late post-CABG using stress myocardial perfusion SPECT: implications of appropriate clinical strategies. J Am Coll Cardiol. 2001;37(1):144–152. â•‡ 46. Arruda AM, McCully RB, Oh JK, Mahoney DW, Seward JB, Pellikka PA. Prognostic value of exercise echocardiography in patients after coronary artery bypass surgery. Am J Cardiol. 2001;87(9):1069–1073. â•‡ 47. Pedone C, Elhendy A, Biagini E, et al. Prognostic significance of myocardial ischemia by dobutamine stress echocardiography in patients without angina pectoris after coronary revascularization. Am J Cardiol. 2008;102(9):1156–1158.

7

Diagnostic Tests for Clinically Suspected Acute Pulmonary Embolism

m enno v. HUiS man In Ge C.m. moS AL BerT De RooS LUcia j.m. KroFT F. A . KLo k

Pulmonary embolism (PE) is a common and potentially fatal condition. Combined with deep vein thrombosis (DVT), it is the third most common cardiovascular disorder in industrialized countries [1]. It is estimated that 350 000 to 600 000 Americans each year suffer from DVT or PE and that at least 100 000 deaths may be directly or indirectly related to these diseases [1]. The diagnostic process of acute PE represents several challenges. Since the symptoms and signs of PE are largely nonspecific, many patients presenting with respiratory or chest symptoms are further investigated but are not found to have PE. Symptoms include dyspnea, pleuritic chest pain, cough, palpitations, and calf pain. Signs include tachypnea, tachycardia, and increased pulmonary tone. Large studies have observed a 20% to 30% incidence of PE in patients with clinically suspected acute PE [2–4], but this incidence is diminishing as the level of suspicion for PE is increasing mainly by a lowering threshold for ordering CT imaging [5]. Accurate and fast identification of the patients who have PE is of great clinical relevance since acute PE is a potentially fatal condition with a 3-month all-cause mortality rate of 6% to 11% in patients with hemodynamically stable PE, and up to 30% or higher in patients with PE presenting with hemodynamic instability or in shock [6–7]. Because of limitations of individual diagnostic tests, many patients are managed on the basis of the results of single diagnostic tools without proper weighing of test results [8–9]. Integrated approaches combining different diagnostic tests and using formal well-validated algorithms are the solution to avoid this problem.

jâ•…C LI NICAL DECISION RULES AND D-DIMER TESTS The positive or negative predictive value of any diagnostic test is dependent on its sensitivity and specificity as well as on the prevalence of the disease in the applied patient population. The negative predictive value of a certain test increases as disease prevalence decreases, and the positive predictive value increases as the disease prevalence increases. Since a diagnostic test for acute PE with 100% sensitivity and specificity is not available, selecting patients according to their clinical probability for PE leads to better performance of the different available diagnostic tests that are used to either reject or establish the diagnosis of PE. The introduction of clinical decision rules for the assessment of pretest probability has led to a standardized evaluation of the pretest probability of patients with Â�suspected PE. The best validated clinical decision rules are the Wells rule (Table 7.1) [10,11] and the Geneva score [12]. Recently, the revised Geneva score (Table 7.1), which is based entirely on clinical variables and is independent of physicians’ implicit judgment, was proposed and Â�validated [13]. All three scores were originally constructed to categorize patients in 3 groups of increasing clinical probability. The scores have comparable predictive value for PE, that is, 4%, 10%, and 8% in the low, 21%, 38%, and 28% in the intermediate, and 67%, 81%, and 74% in the high clinical probability cohort, for the Wells rule, Geneva score, and revised Geneva score, respectively [10,12,13]. Both Wells rule and the revised Geneva score have been dichotomized to increase the clinical utility of the rules. The categorization of patients in “likely” and “unlikely”—in contrast to low, intermediate, and high—clinical probability is clinically more rational, since it facilitates decision making [2]. Recently, both scores have been simplified by awarding one point to all different variables (Table 7.1) [14,15]. Of all patients suspected of PE, 65% and 70% are categorized as PE “unlikely” (prevalence of PE 12% for both) and 35% and 30% are categorized as PE “likely” (prevalence of PE

10 3

Multimodality Imaging in Cardiovascular Medicine

10 4

jâ•… Table 7.1â•… Wells criteria and revised Geneva score Wells Score [11] Items

Score

Revised Geneva Score [13] Simplified Score [21]

Items

Score

Simplified Score [22]

Previous PE or DVT

1.5

1

Age .65 years

1

1

Heart rate .100

1.5

1

Previous DVT or PE

3

1

Recent surgery or immobilization

1.5

1

Surgery or fracture within 1 month

2

1

Clinical signs of DVT

3

1

Active malignancy

2

1

Alternative diagnosis less likely than PE

3

1

Unilateral lower limb pain

3

1

Hemoptysis

1

1

Hemoptysis

2

1

Cancer

1

1

Heart rate $74

3

1

$95

5

2

Pain on lower limb deep vein palpation and unilateral edema

4

1

Clinical probability

Clinical probability

Low

,2

Low

0–3

Intermediate

2–6

Intermediate

4–10

High

.6

High

$11

Dichotomized

Dichotomized

PE unlikely

#4

#1

PE unlikely

#2

PE likely

.4

.1

PE likely

.2

DVT, deep vein thrombosis; PE, pulmonary embolism. From Refs. 11 and 13.

42% and 47%) by the simplified revised Geneva score and the simplified Wells rule, respectively [14,15]. Since both the two- and three-level versions of the rules lack the accuracy of safely ruling out or establishing the diagnosis of PE as a sole test, treatment decisions cannot be made on the basis of a clinical decision rule alone, and hence they are initially combined with a D-dimer test. D-dimer is a degradation product of cross-linked fibrin, and its blood concentration is elevated in acute venous thromboembolic disorders. While the sensitivity of D-dimer for PE is high [16,17], specificity is rather poor

because D-dimer levels can be elevated in all clinical condi tions that are associated with enhanced fibrin formation. These conditions include malignancy, trauma, increased age, disseminated intravascular coagulation, inflammation, infection, sepsis, postoperative states, and preeclampsia. Thus, the potential use of D-dimer tests in patients with suspected acute PE lies in ruling out this disease. When a D-dimer test is applied to a patient population with low or unlikely clinical probability, several large outcome studies using different clinical decisions rules have demonstrated that a normal D-dimer concentration (several different

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assays were studied) is safe to rule out PE with a reported 3 month incidence of symptomatic venous thromboembo lism (VTE, ie, DVT and acute PE) of 0.0 to 0.5% and a reported 3-month PE-related mortality rate of 0.0 to 2.0% (only 1 of 4 large outcome studies reported one recurrent fatal PE in 1660 patients) [2–4,18]. In this way, radiologi cal imaging with contrast agents can be avoided in 30% to 40% of patients [2–4,18]. In contrast, patients with likely clinical probability should undergo further testing regard less of the D-dimer test outcome since VTE can be diag nosed in 9.3% (95% CI 4.8%–17.3%) of the patients with a negative D-dimer test result in this population [19]. Importantly, the threshold for ruling out acute PE varies among the different available assays and does not represent the upper limit of the reference interval in a healthy popula tion [17]. This underlines the need for clinicians to be aware of the particular test used and of its diagnostic cutoff. In addition, only D-dimer assays of which the performance has been confirmed by high-quality prospective outcomes studies should be used as a diagnostic test for acute PE.

jâ•… IMA GING TECHNIQUES Catheter pulmonary angiography is traditionally regarded as the reference imaging method for PE [20–22]. This method, however, is invasive, involves right heart catheter ization and injection of contrast media, and requires con siderable expertise. Of note, a normal result by invasive pulmonary angiography does not fully exclude VTE. The 3-month incidence of recurrent VTE after a normal pulmo nary angiogram has been reported to be 1.7% (95% CI,

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1.0%–2.7%), of which fatal PE occurred in 0.3% (95% CI, 0.02%–0.7%) of the patients [23]. Importantly, it is this 3-month incidence that has become the hallmark against which all clinical outcome studies in PE diagnosis are Â�mirrored. Currently, invasive pulmonary angiography is seldom performed in clinical practice. Ventilation-perfusion (V-Q) scintigraphy (Figure 7.1) has been the imaging method of choice to replace invasive pulmonary angiography for many years. The perfusion scan technique involves the scintigraphic imaging of pulmonary perfusion defects and ventilation scan imaging of the air ways. A negative (normal) perfusion lung scan has a 3-month VTE failure rate of 0.9% (upper 95% CI 2.3%) [24,25]. A high-probability lung scan, that is, a perfusion scan show ing a segmental defect combined with a normal ventilation scan, has a 85% to 90% predictive value for PE [26,27]. The decline of the use of V-Q scintigraphy is primarily due to the high number of nondiagnostic readings in patients with clinically suspected acute PE. In PIOPED I, V-Q scintigraphy gave a definitive diagnosis in 28% of patients [26]. In a more recent study, 46% of patients had a definitive diagnosis by V-Q scintigraphy [4]. Importantly, the prevalence of PE in patients with a nondiagnostic V-Q scintigraphy is 10% to 30%, and further investigation is needed. Computed tomography pulmonary angiography (CTPA) has become the first-line imaging method for assessment of patients with clinically suspected acute PE and is readily available at most hospitals. Pooled data from accuracy stud ies that used single-row detector or 2-row detector CTPA showed a sensitivity of 76% and specificity of 89% [28–34]. The sensitivity proved to be dependent on the location of the embolus in the pulmonary arterial tree: for the main, lobar, or segmental pulmonary artery branches, the sensitivity was

F igure 7 . 1 â•… Ventilation-perfusion (V-Q) scintigraphy showing multiple perfusion defects (upper panels) and homogenous ventilation (lower panels)

diagnostic for pulmonary embolism. V-Q scanning is an excellent method for diagnosing pulmonary embolism when the conventional chest radiograph reveals no cardiopulmonary abnormalities that may limit the use of V-Q scanning.

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jâ•… Table 7.2â•… 64-Row detector computed tomography pulmonary angiography protocol for evaluating patients suspected for having acute pulmonary embolism Preparation

No food or drinks for 3 hours, 18-G needle access in right antecubital vein

Tube voltage

100 kilovolts (kV)

Tube current

Approximately 300 milliampere (mA), modulated in z-direction on noise level of 12.5

Rotation time

0.5 seconds

Helical pitch

53 (0.83)

Field of view

300–400 mm

Scan plan

Lung apices to lateral costophrenic sinus (full chest)

Scan direction

Caudal to cephalic

Scan section thickness

0.5 mm

Reconstruction thickness

0.5 mm

Increment

0.4 mm

Contrast bolus timing and delay

Main pulmonary artery, delay 5 seconds

Iodine content of contrast

400 mg/ml

Injection protocol

80 ml at 4 ml/sec, then 45 ml saline flush at 4 ml/sec

Scan duration

5.9 seconds

Estimated radiation dose

3.4 mSv

Note: Scan protocol for a patient weighing 65–80 kg. Scan parameters and injection protocol are tailored for each patient depending on body habitus.

89% [34–36], while data for distal subsegmental PE indicated a sensitivity of only 21% [34]. Using 4-row detector CTPA, pooled data from two studies showed a sensitivity of 98% and specificity of 94% [37,38]. From these numbers, it can be concluded that with the newer generation of CT scanners, sensitivity to detect PE has increased, without a significant loss in specificity; even more since this increased sensitivity included subsegmental emboli. An important advantage with CTPA is the low number of inadequate imaging, which has varied from 0.9% to 3.0% in large outcome studies [2,4]. The development of and results obtained with multirow detector CTPA has compelled expert panels to conclude that this method has fulfilled the conditions to replace pulmonary angiography as the reference standard [39]. The introduction of multirow detector scanners up to 64-detector rows has further improved helical scanning image quality by means of better temporal and spatial resolution. With 64-row detector CTPA and subsecond gantry rota tion speeds of 0.35 to 0.5 seconds, CTPA can be performed within 4–6 seconds during breath-holding spells. Images can

be reconstructed as thin slices (eg, 0.5–1.0 mm thickness). A 64-CTPA protocol for evaluating patients suspected for hav ing acute PE is shown in Table 7.2 and an example of a patient diagnosed with acute PE by CTPA is shown in Figures 7.2–7.4. A great advantage of CTPA as compared to V-Q scin tigraphy is its ability for finding alternative diagnosis. In patients suspected of having acute PE, alternative diagno ses such as pneumonia or cardiovascular disease that may clinically mimic acute PE are found in 11% to 70% of CTPA examinations [40]. In recent years this has led to the development of dual or triple rule-out protocols, where the major life-threatening conditions, such as PE, acute aortic syndrome, and coronary artery disease, can be evaluated by performing a single electrocardiography (ECG)-gated multidetector computed tomography acquisition. ECG-gated protocols allow sharp reconstruction of the large thoracic vessels (aorta and pulmonary vessels), as well as of the coronary arteries [41]. To keep radiation dose within reasonable limits, ECG-gating with various dose modulation techniques are applied [41,42]. However,

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b

F igure 7 . 2 â•…An 83-year-old female patient with shortness of breath

referred to the emergency department. Computed tomography pulmonary angiography was performed. Axial view (a) and oblique coronal view (b) showing pulmonary embolism (arrows). Embolus load was high and caused right ventricular dilation (a). In the normal situation, the right ventricular diameter does not exceed that of the left ventricle. Also note flattening of the interventricular septum (a). As an incidental finding, a large sliding diaphragmatic hernia was found with the stomach located in the chest (arrowhead). Such a finding may also cause chest discomfort.

F igure 7 . 3 â•… Patient with extended bilateral pulmonary embolism.

F igure 7 . 4 â•… Multirow detector computed tomography scan showing large saddle embolus and enlarged right ventricle.

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ECG-gated protocols still result in higher radiation dose as compared to nongated PE protocols. Also, larger amounts of contrast agent are needed for multiple rule-out proto cols (eg, 120 ml of 370 mg/ml iodinated contrast, or 44.4 g iodine) [41,42] than for dedicated PE protocols (eg, 80 ml of 400 mg/ml or 32 g iodine). The larger amount of contrast is needed for allowing enhancement of the aorta/coronary arteries and pulmonary arteries at the same time. Because of the radiation dose and contrast dose disadvantages, triple rule-out protocols have only been recommended in patients with a high index of suspicion [42]. ECG-gated protocols may also be used for evaluating ventricular function in patients with acute PE. Right ventric ular dysfunction is of concern in patients with acute PE. A low-dose (3.0–4.2 mSv) ECG-gated computed tomography protocol with retrospective reconstruction has been devel oped that allows evaluation of ventricular function in com bination with non-ECG-gated CTPA (2.8–3.9 mSv) [43]. The increase in sensitivity observed with multirow detec tor CTPA has paved the way to management studies evaluat ing diagnostic algorithms in which multirow detector CTPA is used as a sole imaging test to diagnose or rule out PE. CTPA provides an accurate, relatively easy, and widely available imaging modality for evaluating acute PE. Because the accuracy for smaller, subsegmental emboli has increased, this may lead to therapeutic dilemma as the clinical importance and the need for treatment of these emboli is uncertain [44]. There are some disadvantages associated with CTPA. CTPA is relatively contraindicated in patients with renal insufficiency or contrast allergy due to exposure of iodinated contrast material. Also, since the use of CTPA has greatly increased over the previous years, this may lead to a high patient dose that is of special concern in young female patients due to female breast radiation [45]. Unintended radiation dose to the female breast associated with CTPA is tenfold that of a mammographic investigation and hundredfold that of V-Q scintigraphy [46]. Therefore, radiation dose from multidetec tor CTPA has been identified as an important public health issue especially in women of child-bearing potential [47,48]. However, although pregnant patients have been excluded from participation in most clinical outcome studies using CTPA, the calculated radiation dose to the fetus, induced by CTPA, has always been lower than that for V-Q scintigraphy [49,50]. Magnetic resonance pulmonary angiography (MRPA) (Figure 7.5) has attractive potential as an alternative to invasive pulmonary angiography or CTPA in patients with suspected PE in whom it is vital to avoid ionizing radia tion, or who are allergic to iodinated contrast material. Both gadolinium-Â�compound contrast-enhanced and noncontrast-enhanced acquisitions are available for imaging of the pulmonary arteries for detection of acute emboli. The technique used most often is a high spatial resolu tion contrast-enhanced MRPA [51]. Studies in limited number of patients showed sensitivity for the detection of PE with contrast-enhanced MRPA of 77% to 100% and

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Clinically suspected acute PE

CDR unlikely

D-dimer test

CDR likely

Elevated

MD CTPA

Normal 7 . 5 â•… Coronal 3-dimensional magnetic resonance angiogram A, and source image from fourth phase of acquisition B, show filling defect in left lower pulmonary artery, consistent with acute pulmonary embolism. From Ersoy et al, Am J Radiol. 2007;188:1246–1254. F igure

specificity of 95% to 98% [52–54]. In a relatively large study, 118 patients underwent contrast-enhanced MRPA followed by invasive pulmonary angiography [53]. The overall sensitivity of contrast-enhanced MRPA was 77% and specificity was 98%. Although Â�contrast-enhanced MRPA identified all emboli in the central, lobar, and segmental arteries, its sensitivity was only 40% for iso lated subsegmental emboli. Similar results were reported in smaller studies [55,56] and in a study that compared contrast-enhanced MRPA with 16-row detector CTPA as the reference standard [57]. The high specificity allows patients with a positive contrast-enhanced MRPA to be treated for PE with confidence. However, at this time, its sensitivity as a single test is not high enough to reliably exclude PE. Larger, prospective studies, including clinical outcome studies in which a negative contrast-enhanced MRPA is used for excluding acute PE, are needed before the technique is suitable for routine clinical use as the Â�initial imaging test for the evaluation of PE. A study by the PIOPED investigators (PIOPED III) that compares contrast-enhanced MRPA with a composite reference stan dard in a large patient group is currently underway. jâ•… DIAGNOSTIC ALGORITHMS Diagnostic algorithms in PE are a valid tool to reduce the number of CTPA investigations without losing high sensi tivity to rule out clinically relevant disease. As a generally accepted rule such algorithms must yield 3-month VTE failure rates in patients, in whom the diagnosis of PE has been excluded, below 1% to 2% being the rates of DVT and PE at follow-up after negative invasive pulmonary angiography or negative perfusion scintigraphy [58–60]. A diagnostic management strategy using a clinical deci sion and a high sensitive D-dimer test is effective in identify ing patients in whom radiological imaging is not required for safe exclusion of acute symptomatic PE (Figure 7.6), since the (fatal) symptomatic VTE rate in a 3-month follow-up period in patients with a low or unlikely clinical probability

PE ruled out

PE confirmed

No treatment

Treatment

7 . 6 â•…Diagnostic strategy for diagnosing acute pulmonary embolism. PE, pulmonary embolism; CDR, clinical decision rule; MD CTPA, multidetector CT angiography. F igure

in combination with a normal D-dimer test result is very low. In patients who have a clinical probability indicating PE unlikely but an abnormal D-dimer test result, or have a likely or high clinical probability, additional imaging is required to confirm or exclude the diagnosis of PE. If single-row detector CTPA is used as the initial imaging method and PE is not diagnosed, bilateral compression ultra sound (CUS) of the leg veins is needed for ruling out DVT. In two studies that evaluated negative single-row detector CTPA and negative CUS in patients with low or intermediate clinical probability, the observed 3 months VTE failure rate was 0.4% to 1.8% [61,62]. Of note, in these studies CUS was positive for DVT in 15% to 18% of patients with CTPA negative for PE. In two more recent studies, in which the majority of patients had multirow detector CTPA, the yield of additional CUS in patients with CTPA negative for PE was very low (0.9%–1.4%) [4,63]. The combination of clinical probability, D-dimer, and multirow detector CTPA without confirmatory CUS has been successfully used to rule out PE in 3 large cohort follow-up studies [2,3,64]. The feasibility of this integrated algorithm was underlined in one study, in which it could be completed and allowed a management decision in 98% of patients [2]. Finally, in a randomized study where multidetector CTPA was negative for PE, this was found equally safe as a multidetector CTPA negative for PE followed by CUS negative for DVT, with 3-month VTE failure rates of 0.3% in both groups [65]. Finally, there are contradictory results of studies using computed tomography venography of the extremities as an adjunct to CTPA. The sensitivity of detecting VTE with 4-row detector CTPA was increased from 83% to 90% by use of computed tomogra phy venography in combination, but this difference was not significant [66]. However, with 16-row detector CTPA, 16% of patients with suspected PE who were shown to have VTE

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were diagnosed by a positive computed tomography veno gram, although the CTPA was negative for PE [67]. As an alternative to CTPA, V-Q scintigraphy can be used as an initial imaging method in patients with suspected PE. However, the results of the V-Q scintigraphy should be interpreted in combination with the pretest probability for PE. If both clinical decision rules as well as V-Q scintigra phy indicate likely and high probability for PE, the diagnosis is Â�confirmed. When the V-Q scintigraphy is normal and the clinical decision rule indicates PE unlikely, anticoagulation treatment can be withheld. However, when patients have a high-Â�probability V-Q scintigraphy but unlikely pretest prob ability, CUS or CTPA should be considered for advanced evaluation. In patients who have nondiagnostic V-Q scintig raphy, that is, in patients who neither have high pretest prob ability for PE or normal perfusion scan, bilateral CUS of the leg veins is advised [68]. When this CUS is normal and the patient had a clinical probability indicating PE unlikely, PE is excluded. In contrast, if the same patients had a clinical prob ability indicating PE likely, D-dimer test should be performed and acute PE is excluded when normal. If the D-dimer con centration is elevated, a repeat CUS after one week should be performed before treatment can be safely withheld. It is concluded that a diagnostic algorithm with clinical probability assessment, sensitive quantitative D-dimer test ing, and multirow detector CTPA imaging is the standard diagnostic approach in patients with clinically suspected acute PE. A negative D-dimer test in patients with low clin ical pretest probability for PE is safe to rule out PE and avoids radiological imaging with contrast agents in 30% to 40% of patients. As an alternative, V-Q scintigraphy may still be used, although the algorithm is more complicated. Contrast-enhanced MRPA is not yet suitable to be used as a diagnostic imaging test in these algorithms.

jâ•… REFERENCES â•‡ 1.â•‡ US Department of Health and Human Services. The Surgeon General’s call to action to prevent deep vein thrombosis and pulmo nary embolism. 2008. www.hhs.gov â•‡ 2. van Belle A, Büller HR, Huisman MV, et al; for Christopher Study Investigators. Effectiveness of managing suspected pulmonary embo lism using an algorithm combining clinical probability, D-dimer test ing, and computed tomography. JAMA. 2006;2:172–179. â•‡ 3. Goekoop RJ, Steeghs N, Niessen RW, et al. Simple and safe exclu sion of pulmonary embolism in outpatients using quantitative D-dimer and Wells’ simplified decision rule. Thromb Haemost. 2007;1:146–150. â•‡ 4. Anderson DR, Kahn SR, Rodger MA, et al. Computed tomographic pulmonary angiography vs. ventilation-perfusion lung scanning in patients with suspected pulmonary embolism: a randomized con trolled trial. JAMA. 2007;23: 2743–2753. â•‡ 5. DeMonaco NA, Dang Q, Kapoor WN, Ragni MV. Pulmonary embo lism incidence is increasing with use of spiral computed tomography. Am J Med. 2008;121:611–617. â•‡ 6. Nijkeuter M, Söhne M, Tick LW, et al; for Christopher Study Investigators. The natural course of hemodynamically stable pulmo nary embolism: clinical outcome and risk factors in a large prospective cohort study. Chest. 2007;131:517–523.

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â•‡ 7. Wood KE. Major pulmonary embolism. Chest. 2002;121:877–905. â•‡ 8. Schluger N, Henschke C, King T, et al. Diagnosis of pulmonary embo lism at a large teaching hospital. J Thorac Imaging. 1994;9:180–184. â•‡ 9. Kuijer PM, Turkstra F, van Beek EJ, ten Cate JW, Büller HR. A sur vey of the diagnostic and therapeutic management of patients with suspected pulmonary embolism in the Netherlands. Neth J Med. 1997;50:261–266. 10.â•‡ Wells PS, Anderson DR, Rodger MA, et al. Excluding pulmonary embolism at the bedside without diagnostic imaging: management of patients with suspected pulmonary embolism presenting to the emer gency department by using a simple clinical model and D-dimer. Ann Intern Med. 2001;135:98–107. 11. Wells PS, Anderson DR, Rodgers M, et al. Derivation of a simple clinical model to categorize patients probability of pulmonary embo lism: increasing the models utility with simpliRED D-dimer. Thromb Haemost. 2000;83:416–420. 12. Wicki J, Perneger TV, Junod AF, Bounameaux H, Perrier A. Assessing clinical probability of pulmonary embolism in the emergency ward: a simple score. Arch Int Med. 2001;161:92–97. 13. Le Gal G, Righini M, Roy PM, et al. Prediction of pulmonary Â�embolism in the emergency department: the revised Geneva score. Ann Intern Med. 2006;144:165–171. 14. Gibson NS, Sohne M, Kruip MJ, et al for Christopher study investiga tors. Further validation and simplification of the Wells clinical decision rule in pulmonary embolism. Thromb. Haemost. 2008;99:229–234. 15. Klok FA, Mos ICM, Nijkeuter M, et al. Simplification of the revised Geneva score for assessing clinical probability of pulmonary embo lism. Arch Int Med. 2008;168: 2131–2136. 16. Kelly J, Rudd A, Lewis RR, Hunt BJ. Plasma D-dimers in the diagno sis of venous thromboembolism. Arch Int Med. 2002;162:747–756. 17. Righini M, Perrier A, De Moerloose P, Bounameaux H. D-Dimer for venous thromboembolism diagnosis: 20 years later. J Thromb Haemost. 2008;6:1059–1071. 18. Rodger MA, Berdeson CN, Jones G, et al. The bedside investigation of pulmonary embolism diagnosis study: a double-blind random ized controlled trial comparing combinations of 3 bedside tests vs. ventilation-perfusion scan for the initial investigation of suspected pulmonary embolism. Arch Int Med. 2006;166:181–187. 19. Gibson NS, Sohne M, Gerdes VE, Nijkeuter M, Buller HR. The importance of clinical probability assessment in interpreting a nor mal D-dimer in patients with suspected pulmonary embolism. Chest. 2008;134:789–793. 20. Torbicki A, Perrier A, Konstantinides S, et al. Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology. Guidelines on the diagnosis and man agement of acute pulmonary embolism: the Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC). Eur Heart. J. 2008;29:2276–2315. 21. Hudson ER, Smith TP, McDermott VG, et al. Pulmonary angiog raphy performed with iopamidol: complications in 1434 patients. Radiology. 1996;198:61–65. 22. Stein PD, Athanasoulis C, Alavi A, et al. Complications and validity of pulmonary angiography in acute pulmonary embolism. Circulation. 1992;85:462–468. 23. van Beek EJ, Brouwerst EM, Song B, Stein PD, Oudkerk M. Clinical validity of a normal pulmonary angiogram in patients with suspected pulmonary embolism–a critical review. Clin Radiol. 2001;56:838–842. 24. Kruip MJHA, Leclercq MGL, van de Heul C, Prins MH, Büller HR. Diagnostic strategies for excluding pulmonary embolism in clinical outcome studies. Ann Intern Med. 2003;138:941–951. 25. Roy J-M, Colombet I, Durieux P, Chatellier G, Sors Meyer G. Systematic review and meta-analysis of strategies for the diagnosis of suspected pulmonary embolism. BMJ. 2005;331:259–267. 26. The PIOPED Investigators. Value of the ventilation/perfusion scan in acute pulmonary embolism: results of the prospective investigation of pul monary embolism diagnosis (PIOPED). JAMA. 1990;263:2753–2759. 27. Hull RD, Hirsh J, Carter CJ, et al. Pulmonary angiography, ventilation lung scanning, and venography for clinically suspected pulmonary embolism with abnormal perfusion lung scan. Ann Intern Med. 1983;98:891–899.

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28. Qanadli SD, Hajjam ME, Mesurolle B, et al. Pulmonary embolism: prospective evaluation of dual-section helical CT versus selective pul monary arteriography in 157 patients. Radiology. 2000;217:447–455. 29. Drucker EA, Rivitz SM, Shepard JA, et al. Acute pulmonary embolism: assessment of helical CT for diagnosis. Radiology. 1998;209:235–241. 30. Nilsson T, Söderberg M, Lundqvist G, et al. A comparison of spi ral computed tomography and latex agglutination D-dimer assay in acute pulmonary embolism using pulmonary arteriography as gold standard. Scand Cardiovasc. J. 2002;36:373–377. 31. Perrier A, Howarth N, Didier D, et al. Performance of helical com puted tomography in unselected outpatients with suspected pulmonary embolism. Ann Intern Med. 2001;135:88–97. 32. Ruiz Y, Caballero P, Caniego JL, et al. Prospective comparison of heli cal CT with angiography in pulmonary embolism: global and selec tive vascular territory analysis. Interobserver agreement. Eur. Radiol. 2003;13:823–829. 33. Rathbun SW, Raskob G, Whitsett TL. Sensitivity and specificity of helical computed tomography in the diagnosis of pulmonary embo lism: a systematic review. Ann Intern Med. 2000;132:227–232. 34. Van Strijen MJ, De Monye W, Kieft GJ, Pattynama PM, Prins MH, Huisman MV. Accuracy of single-detector spiral CT in the diagnosis of pulmonary embolism: a prospective multicenter cohort study of consecutive patients with abnormal perfusion scintigraphy. J Thromb Haemost. 2005;3:17–25. 35. Remy-Jardin M, Remy J, Wattinne L, Giraud F. Central pulmonary thromboembolism: diagnosis with spiral volumetric CT with the sin gle-breath-hold technique–comparison with pulmonary angiography. Radiology. 1992;185:381–387. 36. Remy-Jardin M, Remy J, Deschildre F, et al. Diagnosis of pulmonary embolism with spiral CT: comparison with pulmonary angiography and scintigraphy. Radiology. 1996;200:699–706. 37. Coche E, Verschuren F, Keyeux A, et al. Diagnosis of acute pulmo nary embolism in outpatients: comparison of thin-collimation multidetector row spiral CT and planar ventilation perfusion scintigraphy. Radiology. 2003;229:757–765. 38. Winer-Muram HT, Rydberg J, Johnson MS, et al. Suspected acute pulmonary embolism: evaluation with multi-detector row CT versus digital subtraction pulmonary arteriography. Radiology. 2004;233:806–815. 39. Remy-Jardin M, Pistolesi M, Goodman LR, et al. Management of suspected acute pulmonary embolism in the era of CT angiography: a statement from the Fleischner Society. Radiology. 2007;245:315–329. 40. Cronin P, Weg JG, Kazerooni EA. The role of multidetector computed tomography angiography for the diagnosis of pulmonary embolism. Semin Nucl Med. 2008;38:418–431. 41. Frauenfelder T, Appenzeller P, Karlo C, et al. Triple rule-out CT in the emergency department: protocols and spectrum of imaging findings. Eur Radiol. 2009;19:789–799. 42. Gallagher MJ, Raff GL. Use of multislice CT for the evaluation of emergency room patients with acute chest pain: the so-called “triple rule-out”. Cathet Cardiovasc Intervent. 2008;71:92–99. 43. Dogan H, Kroft LJ, Huisman MV, van der Geest RJ, de Roos A. Right ventricular function in patients with acute pulmonary embolism: analysis with electrocardiography-synchronized multi-detector row CT. Radiology. 2007;242:78–84. 44. Le Gal G, Righini M, Parent F, van Strijen M, Couturaud F. Diagnosis and management of subsegmental pulmonary embolism. J Thromb Haemost. 2006;4:724–731. 45. Parker MS, Hui FK, Camacho MA. Female breast radiation exposure dur ing CT pulmonary angiography. Am J Roentgenol. 2005;185:1228–1233. 46. Freeman LM, Stein EG, Sprayregen S, Chamarthy M, Haramati LB. The current and continuing important role of ventilation-perfusion scintigraphy in evaluating patients with suspected pulmonary embolism. Semin Nucl Med. 2008;38:432–440. 47. Brenner DJ, Hall EJ. Computed tomography: an increasing source of radiation exposure. N Engl J Med. 2007;357:2277–2284.

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48. Hurwitz LM, Reiman RE, Yoshizumi TT, et al. Radiation dose from contemporary cardiothoracic multidetector CT protocols with an anthropomorphic female phantom: implications for cancer induc tion. Radiology. 2007;245:742–750. 49. Nijkeuter M, Geleijns J, Roos A de, Meinders AE, Huisman MV. Diagnosing pulmonary embolism in pregnancy: rationalizing fetal radiation exposure in radiological procedures. J Thromb Haemost. 2004;2:1857–1858. 50. Winer-Muram HT, Boone JM, Brown HL, Jennings SG, Mabie WC, Lombardo GT. Pulmonary embolism in pregnant patients: fetal radi ation dose with helical CT. Radiology. 2002;224:487–492. 51. Pedersen MR, Fisher MT, van Beek EJ. MR imaging of the pulmonary vasculature—an update. Eur Radiol. 2006;16:1374–1386. 52. Meaney JF, Weg JG, Chenevert TL, Stafford-Johnson D, Hamilton BH, Prince MR. Diagnosis of pulmonary embolism with magnetic resonance angiography. N Engl J Med. 1997;336:1422–1427. 53. Oudkerk M, van Beek EJ, Wielopolski P, et al. Comparison of Â�contrast-enhanced magnetic resonance angiography and conven tional pulmonary angiography for the diagnosis of pulmonary embo lism: a prospective study. Lancet. 2002;359:1643–1647. 54. Gupta A, Frazer CK, Ferguson JM, et al. Acute pulmonary embolism: diagnosis with MR angiography. Radiology. 1999;210:353–359. 55. Meaney JF, Weg JG, Chenevert TL, Stafford-Johnson D, Hamilton BH, Prince MR. Diagnosis of pulmonary embolism with magnetic resonance angiography. N Engl J Med. 1997;336:1422–1427. 56. Gupta A, Frazer CK, Ferguson JM, et al. Acute pulmonary embolism: diagnosis with MR angiography. Radiology. 1999;210:353–359. 57. Kluge A, Luboldt W, Bachmann G. Acute pulmonary embolism to the subsegmental level: diagnostic accuracy of three MRI techniques compared with 16-MDCT, Am J Roentgenol. 2006;187:W7–W14. 58. Hull RD, Raskob GE, Coates G, Panju AA. Clinical validity of a Â�normal perfusion lung scan on patients with suspected pulmonary embolism. Chest. 1990;97:23–26. 59. van Beek EJ, Kuyer PMM, Schenk BE, Brandjes DPM, ten Cate JW, Buller HR. A normal perfusion lung scan in patients with clinically suspected pulmonary embolism: frequency and clinical validity. Chest. 1995;108:170–173. 60. Kipper MS, Moser KM, Kortman KE, Ashburn WL. Long-term follow-up of patients with suspected pulmonary embolism and a normal lung scan. Perfusion scans in embolic suspects. Chest. 1982;82:411–415. 61. Anderson DR, Kovacs MJ, Dennie C, et al. Use of spiral computed tomography contrast angiography and ultrasonography to exclude the diagnosis of pulmonary embolism in the emergency department. J Emerg Med. 2005;29:399–404. 62. Musset D, Parent F, Meyer G, et al. Diagnostic strategy for patients with suspected pulmonary embolism: a prospective multicentre out come study. Lancet. 2002;360:1914–1920. 63. Perrier A, Roy PM, Sanchez O, et al. Multidetector-row computed tomography in suspected pulmonary embolism. N Engl J Med. 2005;352:1760–1768. 64. Ghanima W, Almaas V, Aballi S, et al. Management of suspected pulmonary embolism (PE) by D-dimer and multi-slice computed tomography in outpatients: an outcome study. J Thromb Haemost. 2005;3:1926–1932. 65. Righini M, Le Gal G, Aujesky D, et al. Diagnosis of pulmonary embolism by multidetector CT alone or combined with venous ultrasonography of the leg: a randomised non-inferiority trial. Lancet. 2008;371:1343–1352. 66. Stein PD, Fowler SE, Goodman LR, et al; for PIOPED II Investigators. Multidetector computed tomography for acute pulmonary embo lism. N Engl J Med. 2006;354:2317–2327. 67. Kalva SP, Jagannathan JP, Hahn PF, Wicky ST. Venous thromboembo lism: indirect CT venography during CT pulmonary angiography— should the pelvis be imaged? Radiology. 2008;246:605–611. 68. Wells PS. Integrated strategies for the diagnosis of venous thrombo embolism. J Thromb Haemost. 2007;5(suppl 1):41–50.

8

Contemporary Cardiac Imaging in Dyspnea Due to Heart Failure

Ma rtin St. John Sutton Te d Plappert Ya n Wang

Chronic dyspnea is a common presenting symptom of both cardiac and respiratory failure that is usually preceded by slowly progressive exercise intolerance and fatigue. The specific aims of this chapter are to demonstrate how routinely available cardiac imaging modalities may be used in the diagnosis of heart failure, assessment of its etiology, and differentiation of systolic heart failure from heart failure with normal ejection fraction (diastolic heart failure). Establishing the precise etiology of congestive heart failure (CHF) is important for risk stratification and optimization of treatment strategies that may vary widely with etiology. Noninvasive cardiac imaging has also been used extensively in patients with CHF not only for diagnostic purposes but also for testing the efficacy of new pharmaceutical agents [1–4] and novel technologies, including cardiac resynchronization [5–7], epicardial restraint devices [8], and surgical interventions (mitral valve repair, mitral valve replacement, myocardial revascularization and transplantation), and their impact on clinical outcome. The most common cause of systolic heart failure is coronary artery disease (CAD) [9] and postmyocardial infarction left ventricular (LV) remodeling (Figure 8.1).

F I G U R E 8 . 1 â•…Apical 4-chamber view. The left ventricle is enlarged and the apical myocardium is thin and akinetic in this patient with a remote history of an anterior myocardial infarction.

Coronary heart disease accounts for more than twothirds of the 5 million heart failure patients and a similar proportion of the 500 000 newly diagnosed cases of heart failure each year in the United States alone [10]. Other common causes of heart failure include hypertension (HTN), primary genetically determined hypertrophic and dilated cardiomyopathy (DCM), valvular heart disease, infections including viral myocarditis and bacterial endocarditis, cardiotoxic agents (adriamycin), rarely occurring neurocardiac syndromes, and endocrine disorders that are associated with progressive LV dysfunction and heart failure. The most frequent symptom presentation of chronic CHF is dyspnea, which is often preceded by initially subtle but progressive reduction in exercise capacity, generalized muscle fatigue, weight gain due to fluid retention, dependent edema, cardiac cirrhosis, loss of skeletal muscle mass, and cachexia culminating in death. The terminal stages in the natural history of unrecognized and untreated CHF, which are still occasionally witnessed, are profound oxygen desaturation, orthopnea, paroxysmal nocturnal dyspnea, high-grade life-threatening ventricular arrhythmias, and sudden death, or less commonly, inexorable progression of refractory pump failure and death. Between one-third and one-half of all patients presenting with symptoms of heart failure have normal ejection fraction (HFNEF) [11], formerly known as diastolic heart failure, which may be clinically indistinguishable from systolic heart failure. However, HFNEF is typically more frequent in elderly females with a history of HTN and LV hypertrophy and is characterized by concentric LV remodeling (Figure 8.2). The delay in recognizing HFNEF was due to a number of factors, including the lack of consensus regarding a reliable diagnostic criterion, lack of a reproducible measure of diastolic function, lack of a specific therapy for diastolic dysfunction, and the belief that HFNEF was a benign condition with a favorable prognosis as compared to systolic heart failure. Although the prognosis of heart failure varies with etiology and severity (New York Heart Association Symptom class I through IV), the prognosis of patients with class III heart failure is poor with a mean survival of less than 50% at 5 years from the time of diagnosis [12,13].

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F I G U R E 8 . 2 â•… Parasternal short-axis view. The left ventricular muscle is concentrically hypertrophied in this patient with hypertension and diastolic dysfunction. A small posterior pericardial effusion is also seen (*).

jâ•…D IAGNOSIS OF SYSTOLIC HEART FAILURE AND HFNEF Systolic heart failure occurs when myocardial systolic shortening is so impaired that it fails to deliver blood to meet the metabolic requirements of the body tissues. Although there are numerous causes of chronic systolic heart failure, the cardinal diagnostic changes that occur in LV architecture tend to follow a common pathway or phenotype. This common phenotype of systolic heart failure is characterized by LV dilatation—increased LV end-diastolic and end-systolic chamber size, increased LV load due to inadequate hypertrophy that determines the rate and extent of deterioration in systolic shortening, and an LV ejection fraction ,40% (Figure 8.3). LV dilatation and decreased LV ejection fraction (EF ,40%) can be demonstrated by every contemporary imaging modality. Additional important information can be gleaned from noninvasive cardiac imaging regarding the presence of regional wall motion abnormalities suggesting CAD (Figure 8.4) as the etiology of heart failure and detection of dyssynchrony and mitral regurgitation, which further impact on clinical outcome (Figure 8.5).

F I G U R E 8 . 3 â•… Parasternal short-axis view. The left ventricular cavity is dilated and changes little in size from diastole (left panel) to systole (right panel) in this patient with dilated cardiomyopathy. A left pleural effusion (PL. EFF.) is also demonstrated.

F I G U R E 8 . 4 â•…Apical long-axis view. The left ventricular posterior wall is thin and akinetic as the result of an inferior myocardial infarction.

Heart failure with normal ejection fraction (diastolic heart failure) has multiple etiologies but a common phenotype that is typified by normal LV chamber size, concentric remodeling with increased LV wall thickness, normal systolic shortening, and left atrial (LA) enlargement [14]. The presence of advanced age, female gender, and history of chronic systemic HTN should raise an index of suspicion of diastolic dysfunction. Although the typical phenotypes of systolic heart failure and HFNEF are different, a proportion of patients with CAD may initially develop HFNEF but later transition to systolic heart failure with LV dilatation and low EF (,40%), indicating that there is a degree of fluidity

F I G U R E 8 . 5 â•…Apical long-axis view. Color flow Doppler demonstrates

moderate mitral regurgitation as the color signal extending into the left atrium in this systolic frame.

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rather than rigidity regarding the arbitrary division between the two phenotypes. There is also a less common type of heart failure that is recently becoming recognized that is often called nondilated DCM that is characterized by normal LV size and diminished contractile function (EF ,50%) without concentric hypertrophy [15]. This group of patients may represent an early stage of LV remodeling that antecedes LV dilatation and transition to the systolic heart failure phenotype. The clinical outcome of these patients has not yet been defined. Over the last decade, major advances have been made to our understanding of the mechanisms of LV diastolic dysfunction mainly as a result of novel advances in echocardiographic and Doppler technologies. There is now a portfolio of noninvasive Doppler measurements available to tease out the various effects of abnormal myocardial relaxation from LV loading conditions, LV filling pressures, and chamber stiffness [16]. Evidence for abnormally delayed myocardial relaxation is provided by alteration of the isovolumic relaxation time, that is, the time period between aortic valve closure and mitral valve opening; variation in the peak E wave velocity, the peak A wave velocity, and the E/A velocity ratio as diastolic function transitions from mild to severe and irreversible; and reduction in the deceleration time of the E wave (Figure 8.6). These measurements of LV diastolic function are readily made from Doppler velocity signals recorded from the pulsed-wave sample volume positioned between the tips of the mitral valve leaflets as part of every routine Doppler echocardiogram [16]. Perturbations in the pulmonary venous flow velocity patterns occur due to changes in LV myocardial diastolic dysfunction and filling pressure. The D wave velocity is influenced by changes in LV compliance and mirrors those of the transmitral E wave velocity and increased LV filling pressures, while there is an increase in both the peak amplitude and duration of the atrial reversal velocity wave

F I G U R E 8 . 6 â•… Pulsed-wave Doppler with the sample volume at the tips of the mitral valve leaflets demonstrates the pattern of impaired relaxation with a low-velocity E wave, a high-velocity A wave, and a prolonged deceleration time. The E wave resulting from early left ventricular filling and A wave resulting from atrial Â�contraction are labeled.

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(Figure 8.7). A fall in LA compliance results in a peak Â�systolic to peak diastolic velocity ratio ,1. These velocity signals can also be obtained from the apical 4-Â�chamber view with the sample volume placed ideally 1 cm into either the right or the left superior pulmonary vein. The duration, the peak amplitude of the atrial reversal wave, and the time difference between the durations of and the mitral A wave reflect the presence of diastolic dysfunction and increasing LV end-diastolic pressure. More detailed assessment of diastolic dysfunction can be obtained from color M-mode recorded from the apical 4-chamber view that includes measurement of the LV inflow tract propagation velocity (Figure 8.8) as the slope of the first aliasing velocity, and which Â�correlates with the time constant for LV pressure decay (tau). Recent use of tissue Doppler imaging enables

F I G U R E 8 . 7 â•… Pulmonary venous pulsed-wave Doppler signal. The

velocity of the D wave is reduced. This corresponds to a low-velocity E wave on the transmitral Doppler waveform and typifies the pattern of impaired relaxation. Systolic (S),diastolic (D), and atrial reversal (Ar) waves are labeled.

F I G U R E 8 . 8 â•…The color Doppler M-mode propagation velocity (Vp) is the

slope of an isovelocity line (arrow). This signal is from a normal subject and the Vp is .50 cm/sec.

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early, unequivocal confirmation of diastolic dysfunction by measuring the velocities of the mitral annulus at the Â�septal and lateral walls (Figure 8.9). The ratio of transmitral E to tissue Doppler E9 (E/E9) can be used to predict LV filling pressure because E/E9 correlates closely with LV filling pressures over a wide range of filling pressures. Diagnosis and assessment of LV diastolic function for all practical purposes is virtually exclusively the domain of 2-dimensional (2D) Doppler echocardiography (Figure 8.10).

FIGURE 8.9 â•… Pulsed-wave tissue Doppler with sample volume near the mitral valve annulus adjacent to the LV lateral wall. The E9 wave resulting from early left ventricular filling and A9 wave resulting from atrial contraction are labeled. The E9 velocity is reduced in this patient with a pseudonormal pulsed-wave transmitral Doppler signal.

F I G U R E 8 . 1 0 â•…Transmitral Doppler waveforms, pulmonary venous Doppler waveforms, TDI waveforms, and propagation velocity (Vp) slopes are sketched for normal, impaired relaxation, pseudonormal, and diastolic dysfunction patterns. As diastolic dysfunction progresses from impaired relaxation to diastolic dysfunction, transmitral E wave velocities increase, while pulmonary venous S wave velocities, PW TDI E9 velocities, and propagation velocity decrease.

Multimodality Imaging in Cardiovascular Medicine

jâ•…C ARDIAC IMAGING IN SYSTOLIC HEART FAILURE Epicardial CAD can result in dyspnea from heart failure following acute myocardial infarction due to thrombotic coronary artery occlusion following rupture of an unstable atheromatous plaque [17]. Acute dyspnea occurs because the sudden loss of regional myocyte contractile function causes increased myocardial stiffness of the infarct and adjacent border-zone myocardium, resulting in increased LV filling pressure and transudation of edema fluid into the pulmonary alveoli. Such patients undergo urgent percutaneous cardiac intervention (PCI) to restore myocardial blood flow as quickly as possible by angioplasty and stenting of the stenotic or occluded lesion in the target coronary artery (Figure 8.11). In patients with extensive myocardium at risk and dyspnea due to high LV filling pressures, contrast ventriculography is usually not performed because contrast medium may further increase LV filling pressures in already unstable patients and may precipitate hypotension, renal insufficiency, and occasionally cardiogenic shock. However, images of the causative culprit coronary artery stenosis are recorded at baseline and after PCI for comparison and estimation of residual coronary blood flow (TIMI grade 1–3) to the infarct and the adjacent border-zone pre- and post-PCI. The size, location, and transmurality of the acute myocardial infarction are important predictors of clinical outcome and are easily determined with 2D and 3D echocardiography by the presence of regional wall motion abnormalities that are the hallmark of ischemia heart disease. Between 30% and 35% of survivors of acute myocardial infarction undergo progressive LV remodeling consisting of LV cavity dilatation and distortion that leads to deterioration in contractile function and transition to chronic symptomatic heart failure from months to years after the acute event. The changing LV size, geometry and function, that defines postinfarction LV remodeling has an adverse clinical outcome and comprises the majority of the patients with heart failure and an ischemic etiology. This adverse dynamic LV remodeling process, which culminates in chronic heart

F I G U R E 8 . 1 1 â•… Coronary cineangiogram showing acute closure of the proximal LAD (panel A, arrow). Post-percutaneous cardiac intervention images showing restitution of coronary blood flow (panel B).

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F I G U R E 8 . 1 2 â•… Serial systolic frames in a modified apical 4-chamber

view in a model of ovine anterior wall infarction demonstrate progressive left ventricular remodeling from infarction through eight weeks of follow-up. Image Courtesy of Dr. Robert Gorman and Dr. Joseph Gorman.

failure if unchecked, has been well characterized by serial 2D echocardiography in large randomized clinical trials [1–4]. The time-dependent changes in LV volumes, ejection fraction, and LV mass quantified echocardiographically have been corroborated in experimental studies in animals (Figure 8.12) [18–20] and man by cardiac magnetic resonance (CMR) [21] and computed tomographic angiography (CTA) [22]. These pivotal serial imaging studies have provided important insights that have improved our understanding of LV remodeling and reverse remodeling and the pathogenesis of heart failure of ischemic etiology. However, in contemporary clinical practice, 2D echocardiography is the imaging modality of choice used to study ventricular remodeling that progressed to heart failure presenting with dyspnea initially on exertion but later occurring at rest that can often be rectified by inducing reverse remodeling by pharmacologic intervention or with cardiac resynchronization therapy [5–7].

jâ•…N ONISCHEMIC CARDIOMYOPATHY AS A CAUSE OF DYSPNEA The second most common cardiac cause of systolic heart failure that presents with dyspnea is DCM, 20% to 30% of which is genetically determined primary heart muscle disease (Figure 8.13). There is a wide spectrum of nonischemic cardiomyopathy, the most frequent of which is idiopathic DCM, in which the etiology of the contractile dysfunction is unknown. DCM is most frequently diagnosed by 2D echocardiography in the terminal stages of the disease when the adaptive mechanisms can no longer prevent hemodynamic decompensation and the onset of CHF. DCM is characterized by severe LV cavity enlargement that is associated with alteration in cavity geometry from the normal prolate ellipse to a more spherical shape with a varying degree of left ventricular

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F I G U R E 8 . 1 3 â•…Apical 4-chamber view in a patient with dilated cardiomyopathy. The left ventricle is enlarged and globally hypokinetic.

F I G U R E 8 . 1 4 â•…Diagram illustrating the change in shape from normal

prolate ellipse on the left to spherically remodeled on the right. There is a greater increase in minor than major axis dimensions.

hypertrophy (LVH) (Figure 8.14). This change in cavity architecture causes dilatation of the mitral annulus and disruption of the normal geometry of the mitral subvalve apparatus, resulting in centrally directed mitral regurgitation that further escalates the LV dilatation (Figure 8.15). LV dilatation increases LV loading conditions that determine both the hypertrophic response and also the decrease in contractile performance, as ejection phase indices vary inversely with load, resulting in the onset of heart failure if the increased load is left unchecked. As the LV dilates and contractile function decreases, blood flow velocity decreases within the LV, especially within the LV apex, causing the visual effect of smoke. This increases the propensity to form intracavity thrombus on regions of myocardium that are severely hypokinetic, thereby increasing the likelihood of systemic thromboembolism and stroke (Figure 8.16) [23]. Detection of intracardiac thrombus is of the greatest importance to avoid stroke and its devastating consequences. Whether Doppler echo or CMR is used, a thorough search for thrombus in all patients with DCM especially of ischemic etiology is mandatory. Intravenous injection of echo contrast such as Definity (Figure 8.17) can be used to enhance the accuracy of the diagnosis of LV thrombus by improving endocardial

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F I G U R E 8 . 1 7 â•…A magnified apical 4-chamber view demonstrates an apical mural thrombus (arrow) highlighted by echo-contrast material. The thrombus was not appreciated by conventional imaging. 8 . 1 5 â•…Apical 4-chamber view showing severe centrally directed mitral regurgitation by color flow Doppler in a patient with dilated cardiomyopathy.

FIGURE

F I G U R E 8 . 1 6 â•…A large laminated apical mural thrombus is seen in the

apical 4-chamber (left) and apical long-axis views.

definition so that therapeutic intervention with heparin and initiation of oral anticoagulation with coumadin can be instituted. Development of chronic mitral regurgitation in DCM results in LA enlargement, pulmonary venous HTN and vaso-reactive pulmonary arterial HTN, RV dilatation and dysfunction, tricuspid regurgitation (Figure 8.18), and finally right atrial enlargement so that there is often 4-chamber dilatation and biventricular failure. These diagnostic features are demonstrated equally well by echo CMR and CTA, although color flow Doppler is exquisitely

F I G U R E 8 . 1 8 â•… Color flow Doppler illustrates moderately severe tricus-

pid regurgitation in this apical 4-chamber view in a patient with dilated cardiomyopathy and 4-chamber enlargement.

sensitive to mitral regurgitation. One cause of LV dilatation, increased wall thickness, and global LV dysfunction that can be diagnosed easily by CMR is hemochromatosis because of the increased iron content that makes the LV walls in the apical 4-chamber and short-axis views almost glow. Systemic HTN induces LV hypertrophy via the AT1

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receptor. Deformation of the cell surface by increased loading conditions is transduced by cell surface mechanoreceptors/integrins, resulting in concentric hypertrophy and remodeling that is indistinguishable from nonobstructive hypertrophic cardiomyopathy (HCM). However, long-standing poorly controlled decompensated systemic HTN can closely resemble nonischemic DCM.

jâ•…H CM AS A CAUSE OF DYSPNEA Idiopathic HCM is an autosomal dominantly inherited genetic disorder in which a similar phenotype derives from a number of mis-sense mutations in the sarcomeric proteins. Since the first gene locus was identified on the -myosin heavy-chain (-MyC on 14q1), mis-sense point mutations have been localized to cardiac troponin I and C, myosin-binding protein C, and cardiac -actin and titin that modulate cytosolic calcium handling by altering the convolutional changes in the tertiary structural relationship of the contractile protein interaction during contraction. Although the genotype varies widely with regard to the location of the mis-sense mutation, the phenotypes are relatively consistent. HCM is typified by LV hypertrophy and unique chamber architecture, which includes regional variability in hypertrophy that affects predominantly the interventricular septum (Figure 8.19) known as asymmetric septal hypertrophy (ASH). The ASH often encroaches upon the LV outflow tract, which together with the anterior displacement of the mitral valve by the hypertrophy of the posterior wall and inferobasal papillary muscles results in systolic anterior motion of the mitral valve (Figure 8.20). This further narrows the LV outflow tract, causing dynamic gradients at rest that usually augment on exertion and with Valsalva maneuver (Figure 8.21). The altered mitral geometry is associated with development of mitral regurgitation of varying severity. The etiology of dyspnea is complex due to the interaction of a number of important contributing factors, including mitral regurgitation of varying severity (Figure 8.22), increased LV

F I G U R E 8 . 2 0 â•… Parasternal long-axis view. Asymmetric septal hyper-

trophy and systolic anterior motion of the mitral valve (arrow) are demonstrated.

F I G U R E 8 . 2 1 â•… Continuous-wave Doppler of the left ventricular outflow

tract in a patient with hypertrophic obstructive cardiomyopathy. The peak velocity of 4.5 m/sec represents a peak gradient of approximately 81 mm Hg.

8 . 2 2 â•… Parasternal long-axis view. Moderately severe mitral regurgitation (MR) is present in this patient with hypertrophic cardiomyopathy.

FIGURE F I G U R E 8 . 1 9 â•… Parasternal short-axis view. There is marked asymmet-

ric septal hypertrophy in this patient with hypertrophic cardiomyopathy.

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chamber stiffness from the extensive hypertrophy, and diastolic myocardial dysfunction. All these factors are associated with increased LV filling pressure that in turn results in elevation of LA and pulmonary venous pressures, leading to symptoms of chronic progressive dyspnea culminating in pulmonary arterial HTN. The diagnosis of HCM is usually established by 2D echocardiography, by the presence of a normal to underfilled LV cavity, severe ASH, and systolic anterior motion of the mitral valve causing LV outflow tract obstruction with early closure of the aortic valve signifying the end of systolic ejection in the first-third to onehalf of systole. The division of patients into obstructive and nonobstructive HCM in the presence of a resting LVOT gradient is a little arbitrary because a proportion of patients without resting gradients may develop dynamic systolic LV outflow tract gradients with isometric exercise (handgrip) or with provocation by physiologic maneuvers such as Valsalva. The resting and provocable gradients can be obtained with continuouswave Doppler. The diagnosis can be equally well established by CTA and MRA and the gradients estimated. Hypotension during stress testing, end-diastolic septal thickness .3.0 cm, syncope, ventricular tachycardia, and precocious cardiac deaths of first-degree relatives are all risk factors for sudden cardiac death, syncope, and indications for ICD placement.

jâ•…H TN, LV HYPERTROPHY, AND HEART FAILURE Chronic HTN, if unrecognized or inadequately treated, results in concentric LV remodeling with LVH that usually causes similar increase in the free LV wall and interventricular septal thicknesses, so that myocardial force development is distributed uniformly throughout the LV

F I G U R E 8 . 2 3 â•… Parasternal short-axis view. There is concentric left ven-

tricular hypertrophy and moderately diminished systolic function in this patient with hypertension.

Multimodality Imaging in Cardiovascular Medicine

walls (Figure 8.23). LVH in HTN represents an attempt to normalize LV wall stress and preserve contractile function. Inadequate elaboration of LVH fails to normalize load and permits progressive LV dilatation and transition from concentric to eccentric remodeling. Chronic severe hypertensive heart disease may resemble the genetically programed LVH in hypertrophic nonobstructive cardiomyopathy. Noninvasive imaging with 2D echo, MRI, and CT can define the abnormal LV architecture and quantify LV mass and LV function. Furthermore, the impact of antihypertensive agents on LV mass reduction and the effects on remodeling can be tracked over time to establish the efficacy of individual drug therapy. In practice, most studies of LVH regression have used 2D echocardiography even though CMR is acknowledged to be the gold standard for LV estimation of LV mass and volume. MRI estimates of LV mass are less varied and more reproducible than the estimates made by 2D echo, and therefore, smaller patient cohorts can be studied to obtain the same clinical end point.

jâ•…R ES TRICTIVE CARDIOMYOPATHY The most common type of restrictive cardiomyopathy in the United States is cardiac amyloidosis, which occurs due to intermyofibrillar deposition of noncontractile protein consisting of immunoglobulin lightchain dimers. Patients with cardiac amyloid may present at any age, usually with dyspnea, fatigue, and lower extremity edema, and typically have preserved or only mildly decreased LV systolic function (LVEF) early in the course of the disease, but discrepantly severe diastolic dysfunction (Figure 8.24) [24]. The LV cavity is invariably normal size with markedly increased wall thickness but low voltage on electrocardiogram. Transmitral flow velocity signals are characterized by

F I G U R E 8 . 2 4 â•… Parasternal long-axis view showing concentric left ventricular hypertrophy and decreased systolic function in a patient with amyloid cardiomyopathy.

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deterioration in LV function without the compensatory LV cavity dilatation. The progressive decline in LV function is heralded by the onset of increasing shortness of breath that may develop over weeks to years when overt heart failure occurs. There are no specific imaging features or stigmata of adriamycin toxic cardiomyopathy, and the baseline assessment of LVEF and surveillance studies are almost invariably obtained using serial echocardiograms. The presence of severe symptomatic heart failure with a normal end-diastolic volume should raise the possibility of chemotherapeutic toxicity that can be confirmed by the patient’s clinical history.

F I G U R E 8 . 2 5 â•…A restrictive filling pattern of transmitral pulsed-wave

Doppler, characterized by an elevated E wave and E/A ratio and short deceleration time, is present in this patient with amyloid cardiomyopathy.

E/A wave velocity reversal (Figure 8.25), a shortened E wave deceleration time (,140 millisecond), abnormal pulmonary venous flow, decreased propagation velocity due to increased LV chamber, and myocardial stiffness [25] from the accumulation of noncontractile protein that changes the material properties of the myocardium to which the loss of myocytes from pressure necrosis contributes. The characteristic amyloid phenotype consists of normal LV cavity size, increased septal and free LV wall thickness, enhanced myocardial acoustic signature, nonspecific thickening of the cardiac valves, increased interatrial septal and RV wall thicknesses, and usually a small hemodynamically unimportant pericardial effusion. When these major LV remodeling changes coupled with the grossly abnormal diastolic function are present, the diagnosis can be made unequivocally and confirmed by gingival biopsy that is recommended for definitive tissue diagnosis. The abnormal structural and functional remodeling described by echocardiography above can be obtained equally well by CMR and CTA.

jâ•…LV INFLOW TRACT OBSTRUCTION AS A CAUSE OF DYSPNEA Although the incidence of rheumatic valvular heart disease has declined over the last five decades in the United States, patients from the third world are frequently encountered with unsuspected moderate to severe rheumatic mitral stenosis who present with dyspnea and progressive reduction in exercise capacity. The severity of dyspnea varies with mitral valve orifice area, transvalve diastolic pressure gradient, and the degree of secondary pulmonary arterial HTN. This chronic dyspnea may worsen acutely with the onset of atrial fibrillation and a rapid ventricular rate response that is the natural history of rheumatic mitral valve disease. The diagnosis is usually made by 2D echocardiography, demonstrating fusion and cicatrization of the mitral valve commissures that is pathognomic of rheumatic mitral valve disease. Doppler echocardiographic imaging in multiple planes shows the characteristic restricted leaflet motion, the thick shortened chordae, LA enlargement, and pulmonary HTN and allows assessment of the hemodynamics that enable estimation of the mitral valve orifice area (Figure 8.26). Nonrheumatic LV inflow tract obstruction may also occur due to extensive mitral annular calcification that may immobilize the posterior leaflet and to a less extent

jâ•…C ARDIOTOXIC AGENTS Chemotherapeutic agents, especially analogs of adriamycin/ daunorubicin used in the treatment of solid tumors may be cardiotoxic even within the therapeutic dose range and may result in severe irreversible LV dysfunction. Typically, there is little or no end-diastolic LV dilatation but severely decreased myocardial shortening, resulting in a precipitous drop in stroke volume and inability to modulate stroke volume, so that the only remaining physiologic mechanism available to increase cardiac output is by increasing heart rate. The presence of persistent sinus tachycardia escalates the

F I G U R E 8 . 2 6 â•… Parasternal long-axis view in a patient with mitral steno-

sis. The mitral valve is thickened and immobile. The left atrium is enlarged.

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Multimodality Imaging in Cardiovascular Medicine

F I G U R E 8 . 2 7 â•… Parasternal long-axis view. There is extensive mitral

annular calcification (arrow) causing mild mitral stenosis.

F I G U R E 8 . 2 8 â•… Parasternal long-axis view. There is prolapse of the pos-

terior mitral valve leaflet (arrow).

the anterior mitral leaflet, thereby narrowing the mitral valve orifice and splinting the mitral subvalve apparatus (Figure 8.27). Mitral annular calcification causing stenosis of the mitral valve orifice is usually encountered in elderly female patients, particularly those with impaired calcium handling from renal insufficiency or from concomitant calcific aortic stenosis.

jâ•…C ONGENITAL HEART DISEASE AS A CAUSE OF DYSPNEA The two rare congenital cardiac anomalies also usually presenting with dyspnea due to LV inflow tract obstruction/ mitral stenosis are cor triatriatum and supravalvar mitral membrane and a parachute mitral valve as part of the Shone’s complex of multiple left-sided stenoses. Development of dyspnea results from the diastolic pressure gradient across the LV inflow tract initially causing pulmonary venous HTN, pulmonary vascular remodeling, and finally pulmonary arterial HTN in an exactly similar paradigm as in rheumatic mitral stenosis. Dyspnea in rheumatic mitral stenosis is insidious and may not be appreciated until the sudden onset of atrial fibrillation with initially rapid ventricular response. Clinical examination in severe rheumatic mitral stenosis should establish the diagnosis and 2D Echo serves to quantitate its severity in terms of pressure gradients and effective valve orifice area.

jâ•…A TRIO-VENTRICULAR VALVE REGURGITATION AS A CAUSE OF DYSPNEA Mitral regurgitation due to primary degenerative mitral valve disease, ischemic heart disease, or functional as a consequence of altered mitral valve geometry secondary to LV dilatation are all associated with dyspnea when sufficiently severe. The incidence of degenerative mitral valve disease increases with age and is characterized by floppy

F I G U R E 8 . 2 9 â•…Apical 4-chamber view showing moderately severe

mitral regurgitation by color flow Doppler.

myxomatous leaflets (Figure 8.28), redundant tensor apparatus that allows leaflet prolapse in systole causing traction and frequent rupture of the chordae tendineae, escalation of the eccentric mitral regurgitation, and mitral annular dilatation. 2D and 3D transthoracic Doppler echocardiography are the imaging modality of choice for diagnosis and assessment of the severity of mitral regurgitation (Figure 8.29). Furthermore, if surgical repair is contemplated, preoperative transesophageal Doppler echocardiography should be performed to determine whether mitral valve repair is feasible, and if so, what additional procedures are necessary including quadrangular leaflet resection, chordal shortening, or placement of neochordae. Ischemic mitral regurgitation has a poor prognosis [26] and may be overlooked or seriously underestimated if Doppler echocardiographic imaging is performed at rest

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only, without an intervention to increase after load such as isometric handgrip or a formal exercise protocol. The mitral valve leaflets and subvalve apparatus are typically intrinsically normal and the mitral annulus is not enlarged. Often, regional wall motion abnormalities are present especially involving the inferoposterior wall that disrupt the normally exquisite temporal coordination of the mitral valve apparatus during leaflet coaptation and closure, causing leaflet tenting and mitral regurgitation that may vary from mild to severe. Mitral regurgitation should ideally be quantified by Doppler using proximal isovelocity surface area techniques (Figure 8.30) to assess mitral regurgitant volume and regurgitant orifice area at rest and with exercise and pulmonary arterial pressure should be estimated from the tricuspid regurgitant jet (Figure 8.31) at the same time points. Functional mitral regurgitation occurs as a result of LV dilatation from any cause, may vary from mild to severe, and may precipitate hemodynamic instability, leading to heart failure and abrupt increase in dyspnea. LV dilatation is associated with greater increase in the LV short-axis diameter than long-axis length so that the cavity becomes more spherical, thereby enabling greater increase in LV end-diastolic volume per unit circumference. This change in LV architecture separates the papillary muscles without any change in length of the mitral leaflet or chordae, which, concomitant with the dilated mitral annulus, reduces the area of leaflet coaptation, resulting in mitral regurgitation. All the stigmata of secondary mitral regurgitation can best be demonstrated in echocardiographic images of the LV

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from the parasternal short-axis and the apical 4-chamber views. Quantification of the severity of mitral regurgitation is achieved routinely by proximal isovelocity surface area as regurgitant volume and effective regurgitant mitral orifice area. Mitral regurgitation presenting with dyspnea should increase suspicion for vegetative endocarditis, which is sometimes more chronic than acute with less virulent streptococcal and coagulase-negative staphylococcal infections and is not accompanied by the typical clinical findings on examination or when cursory antibiotic use has resulted in negative blood cultures. Mitral valve vegetations may be obvious on routine transthoracic echocardiography as mobile, shaggy masses attached to the LA surface of the mitral leaflets (Figure 8.32) with hemodynamically important mitral regurgitation. In contrast, there may be nonspecific mitral leaflet thickening with little or no mitral

8 . 3 1 â•…This continuous-wave Doppler signal of tricuspid regurgitation has a peak velocity of 3.5 m/sec, which represents a systolic pressure gradient between the right ventricle and right atrium of 49 mm Hg.

FIGURE

FIGURE 8.30â•…Transesophageal 4-chamber view in a patient with

mitral regurgitation. Regurgitant volume and regurgitant orifice area can be calculated using the proximal isovelocity surface area method. The color Doppler signal aliases each time the flow velocity exceeds a multiple of the Nyquist limit, resulting in a series of concentric hemispheres of alternating color. The cross-Â�sectional area of the proximal hemisphere is determined from the measured radius [2π (r 2)] and the regurgitant orifice area is determined by the continuity equation.

F I G U R E 8 . 3 2 â•… Parasternal long-axis view. Vegetation is demonstrated as a shaggy mass attached to the left atrial aspect of the anterior mitral valve leaflet.

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regurgitation. In the latter circumstance, if there is still a high index of suspicion for endocarditis, then transesophageal echocardiography should be considered for diagnostic clarification because vegetations can be identified or excluded with 95% confidence.

jâ•…S EMILUNAR VALVULAR REGURGITATION AS A CAUSE OF DYSPNEA Aortic regurgitation usually presents with diminished exercise capacity and dyspnea that may result from congenital anomalies of the aortic valve, including bicuspid (Figure 8.33) and unicuspid valve leaflets, myxomatous leaflets, aortic aneurysms associated with connective tissue disorders such as Marfan syndrome (Figure 8.34), or with perimembranous ventricular septal defects causing traction and deformation of the aortic valve leaflets. Aortic regurgitation may also be acquired such as rheumatic valvulitis, ascending aortic root aneurysm Â�including type A aortic dissections, and also with aortic valve vegetative endocarditis.

Multimodality Imaging in Cardiovascular Medicine

In more than 95% of patients examined, the anatomy of the valve leaflets and commissures and leaflet anatomy can be discerned both in short and long axis by 2D and 3D transthoracic and transesophageal Doppler echocardiography. Detection of vegetative endocarditis by transthoracic echo is critically important and can be achieved unequivocally in up to 70% of patients with transthoracic echo and close to 95% by TEE. Chronic aortic regurgitation presenting with dyspnea is easily recognized because color flow Doppler is exquisitely sensitive to minor flow disturbances in the LV outflow tract due to even trivial aortic regurgitation (Figure 8.35). Doppler echocardiography has an important role in the assessment of the severity of aortic regurgitation in terms of LV size, ejection fraction, regurgitant fraction, and effective regurgitant orifice area. These echocardiographic measurements determine the optimal timing of valve replacement.

jâ•…S EM ILUNAR VALVE STENOSIS AS A CAUSE OF DYSPNEA Aortic stenosis may present in adulthood in the fifth to sixth decade resulting from calcification of a bicuspid aortic valve or in the seventh to ninth decade as severe calcific degenerative stenosis of a trileaflet aortic valve (Figure 8.36). Approximately one-third of patients develop symptoms of exercise intolerance and dyspnea that heralds the onset of decompensated heart failure and has a poor prognosis with a 50% survival at 3 years after diagnosis. Dyspnea may occur in combination with chest pain and/or syncope. In terminal/end-stage severe aortic stenosis, the typical clinical signs are attenuated so that the diagnosis may be overlooked because the apical impulse is diffuse

F I G U R E 8 . 3 3 â•… Parasternal short-axis view of a bicuspid aortic valve.

The aortic valve appears to be trileaflet in the diastolic frame but there is a raphe between the apparent right and left coronary cusps.

F I G U R E 8 . 3 4 â•…Apical long-axis view in a patient with Marfan’s syn-

drome. The aortic root is markedly dilated. Mitral valve prolapse is also seen (arrow).

F I G U R E 8 . 3 5 â•… Parasternal long-axis view with color flow Doppler dem-

onstrating severe aortic regurgitation in this diastolic frame.

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leaflets often extends into the mitral valve annulus. HemoÂ� dynamic assessment of the severity of aortic Â�stenosis is the domain of Doppler echocardiography, with which peak and mean systolic gradients that enable quantification of aortic valve orifice area are obtained (Figure 8.38). Aortic valve orifice area should be estimated in every patient with suspected severe aortic stenosis because Â�reliance on transvalve gradients alone in patients with LV dysfunction will fail to diagnose critical aortic stenosis. F I G U R E 8 . 3 6 â•… Parasternal long-axis (LAX) and short-axis (SAX) images

from a patient with moderately severe calcific aortic stenosis. The trileaflet nature of the valve can be seen in the right panel.

F I G U R E 8 . 3 7 â•… Parasternal long-axis view in a patient with severe aor-

tic stenosis and severe concentric left ventricular hypertrophy.

and displaced, indicating LV dilatation and decreased contractile performance. The characteristically loud, harsh ejection systolic murmur in decompensated aortic stenosis may be almost inaudible due to the severely decreased cardiac output. Furthermore, diagnosis of aortic stenosis allows for timely operative intervention without which the natural history is bleak [27]. Noninvasive imaging is invariably by 2D echocardiography, which demonstrates calcified immobile valve leaflets with severe reduced opening (Figure 8.37). In senile aortic stenosis, calcification of the aortic valve

F I G U R E 8 . 3 8 â•…This continuous-wave Doppler signal of aortic stenosis has a peak velocity of 5 m/sec, which equates with a peak gradient of 100 mm Hg.

jâ•…I NT RACARDIAC SHUNTS AT ATRIAL LEVEL AS A CAUSE OF DYSPNEA The majority of adults with undiagnosed atrial septal defects (ASDs) are asymptomatic and are recognized only by detection of a heart murmur or by the presence of right bundle branch block on the electrocardiogram or the serendipitous radiographic findings on chest radiograph of an enlarged right atrium and right ventricle, shunt vascularity, and a small aortic knuckle. However, a minority of adults with a left to right shunt at atrial level and pulmonary to systemic flows .1.5:1.0 L/min complain of dyspnea, exercise intolerance, and a history of recurrent respiratory infections throughout childhood. Chronically increased pulmonary blood flow from a shunt at atrial level may be due to defects in the atrial septum of secundum, primum, and sinus venosus types or due to an unroofed coronary sinus. The diagnosis of the different types of ASDs can be made unequivocally by transthoracic echocardiography, although sometimes sinus venosus defects can be challenging. In sinus venosus ASDs, precise localization of the course of associated anomalous pulmonary veins may require CT or MR angiographic imaging prior to surgical intervention [28]. The 2D and 3D echocardiography provides information regarding the location, size of the ASD, the hemodynamics in terms of shunt flow, pulmonary artery systolic pressure, and the extent of right atrial and ventricular remodeling (Figure 8.39).

F I G U R E 8 . 3 9 â•…A modified apical 4-chamber view from a patient with

a large secundum atrial septal defect (*). The right heart chambers are greatly enlarged.

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FIGURE 8.40â•…Diastolic parasternal long-axis (left panel) and shortaxis (right panel) views from a patient with a large circumferential pericardial effusion (EFF). Right ventricular (RV) indentation (arrows) in diastole indicating that pericardial pressure exceeds right ventricular filling pressure is evidence of tamponade.

Multimodality Imaging in Cardiovascular Medicine

F I G U R E 8 . 4 1 â•…A large left pleural effusion (PL) is seen in this parasternal long-axis view from a patient with dilated cardiomyopathy. Pleural effusions are posterior to the descending thoracic aorta (DA) in this projection.

Rarely, patients with ASDs present later in life complaining of dyspnea that is secondary to pulmonary HTN due to pulmonary vascular disease with dependent edema, tricuspid regurgitation, pulsatile hepatomegaly, and right heart failure. ASDs should be considered in the diagnosis of dyspnea in heart failure as a potentially reversible cause of dyspnea.

jâ•…P ERICARDIAL AND PLEURAL EFFUSION AS A CAUSE OF DYSPNEA Large chronic pericardial effusions and large pleural effusions that are slow to accumulate are often due to metastatic spread of malignant tumors including lung, esophagus, breast, melanoma, and lymphoma. Such patients may present with pericardial tamponade (Figure 8.40) complaining of shortness of breath, easy fatigue, and Â�sensation of fullness in the central Â�precordium. The Â�diagnosis of pericardial effusion is often Â�suggested by the large heart silhouette and configuration on chest Â�radiograph. Patients with large and/or Â�bilateral Â�pleural effusions may also present for medical Â�attention, Â�complaining of shortness of breath that can be Â�unequivocally diagnosed and distinguished from Â�pericardial effusions by Â�echocardiography at the bedside (Figure 8.41). 2D echo cannot only establish the diagnosis but also approximate the volume/size of the effusion and determine whether there is sufficient clearance for percutaneous pericardiocentesis. Chest CT is also very reliable for imaging pericardial effusions in patients with dyspnea in whom 2D echocardiographic images are technically limited or nondiagnostic. However, when high-quality echo images are obtained, they provide hemodynamic information regarding the severity of the pericardial effusion that is unavailable from chest CT (Figure 8.42).

F I G U R E 8 . 4 2 â•… Pulsed wave (PW) Doppler with the sample volume at

the tips of the MV leaflets in a patient with cardiac tamponade. There is marked variation in transmitral flow velocities. The E wave velocity increases phasically with expiration and decreases with inspiration.

jâ•…P ULMONARY EMBOLISM AS A CAUSE OF DYSPNEA The combination of chest pain and dyspnea can also result from acute severe pulmonary embolism that is in the clinical differential diagnosis of acute chest pain syndrome. Differentiation of an acute pulmonary embolism from acute infarction rarely poses a diagnostic problem because infarction can be resolved by an abnormal ECG and elevated cardiac enzyme. Definitive diagnosis of pulmonary embolism can be made by selective pulmonary contrast angiography or more commonly by CT angiography as regional pulmonary arterial perfusion defects, by nuclear ventilation/perfusion mismatch with dual isotopes, and indirectly by echocardiography as the presence of the dilated and severely hypokinetic right ventricle and the hyperdynamic underfilled LV. However, a small proportion of patients with peripheral deep venous thrombosis have recurrent episodes of thromboembolism often without a clinical event and progress to severe thromboembolic pulmonary hypertension. Such patients usually present with chronic progressive dyspnea, right heart failure with lower extremity edema, cardiac cirrhosis,

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discrepantly severe dyspnea, raising the clinical suspicion for combined heart and lung disease. Parenchymal lung disease includes progressive impairment of respiratory gas exchange kinetics due to loss of alveoli or interstitial fibrosis, which may present with dyspnea and severe right heart failure. In the majority of cases of primary lung disease presenting with chronic severe dyspnea, chest CT is diagnostic (Figure 8.44).

jâ•…C ON CLUSIONS

F I G U R E 8 . 4 3 â•… Parasternal short-axis view showing the aorta (AO) and pulmonary artery (PA). A thrombus (arrow) is demonstrated straddling the bifurcation of the pulmonary artery.

ascites, systemic hypotension, and hypoxemia. The diagnosis of chronic thromboembolic pulmonary hypertension is initially suggested echocardiographically by the severely dilated RV that forms the apex of the heart, poor RV function, and a clinical history of recurrent DVT. Definitive diagnosis is established by CT angiography (Figure 8.43).

jâ•…PARENCHYMAL LUNG DISEASE AS A CAUSE OF DYSPNEA A number of primary lung disorders including emphysema may coexist with coronary heart disease and share risk factors such as tobacco use may present with chest pain and

Dyspnea is a cardiovascular symptom that should be taken seriously and its cause fully investigated. Dyspnea may result from primary or acquired myocardial dysfunction, from LV outflow obstruction and regurgitation at aortic valve level, from LV inflow tract obstruction due to rheumatic or nonrheumatic mitral stenosis, and from pulmonary arterial HTN due to parenchymal lung disease or chronic recurrent thromboembolism. In the majority of patients presenting with dyspnea, the clinical history and physical examination point to a specific disease process, in which case the mode of noninvasive imaging can be selected and used to confirm the diagnosis and determine the severity of the disease. By contrast, in the minority of patients in whom the diagnosis remains uncertain after obtaining a detailed clinical history and examination, imaging should be focused on the most likely etiology to avoid multimodality pan-imaging bonanzas. In such patients without the typical cardiac murmurs of mitral and/or artic valve disease, attention should turn first to assessment of LV dysfunction and subsequent elucidation of its precise etiology by coronary arteriography, for example. Patients with pulmonary disease presenting with dyspnea and oxygen desaturation without cyanotic complex congenital heart disease are best investigated with CTA or CMR that can exclude intracardiac shunts at atrial level and identify causative pulmonary parenchymal disease and pulmonary vasculitides.

F I G U R E 8 . 4 4 â•… Chest computed tomography showing severe interstitial pulmonary fibrosis from a 60-year-old patient with severe dyspnea and central

precordial chest pain that progressed over a period of 9 months. Chest Â�computed tomography established the unequivocal diagnosis of interstitial pulmonary fibrosis, demonstrating severe and extensive destruction of the lung parenchyma.

Multimodality Imaging in Cardiovascular Medicine

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Finally, noninvasive imaging is expensive and should be used prudently, not simply to confirm a certain clinical diagnosis but to assess the severity of the LV dysfunction and determine whether alternative or surgical interventions are indicated. The era of defensive medicine is behind us, and unnecessary repetitive multimodality imaging with no prospect of a new diagnosis is reprehensible, fiscally irresponsible, and inconsistent with optimal medical practice.

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jâ•…R EFERENCES â•‡ 1. The SOLVD Investigators. Effects of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med. 1992;327:685–691. â•‡ 2. Pfeffer MA, Braunwald E, Moye LA, et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and Â�ventricular enlargement trial. The SAVE Investigators. N Engl J Med. 1992;327:669–677. â•‡ 3. Bristow MR, Krause-Steinrauf H, Nuzzo R, et al. Effect of baseline or changes in adrenergic activity on clinical outcomes in the -blocker evaluation of the survival trial. Circulation. 2004;110:1437–1442. â•‡ 4. Anderson RE, Pfeffer MA, Thune JJ, et al. High-risk myocardial infarction in the young: the VALsartan in Acute myocardial infarction (VALIANT) trial. Am Heart J. 2008;155(4):706–711. â•‡ 5. Abraham WT, Fisher WG, Smith AL, et al. Cardiac resynchronization in chronic heart failure. N Engl J Med. 2002;346:1845–1853. â•‡ 6. Cleland JG, Daubert JC, Erdmann E, et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med. 2005;352:1539–1549. â•‡ 7. Moss AJ, Hall WJ, Cannom DS, et al; for the MADIT-CRT Trial Investigators. Cardiac resynchronization therapy for the prevention of heart failure events. N Engl J Med. 2009;361:1–10. â•‡ 8. Mann DL, Acker MA, Jessup M; for Acorn Trial Principal Investigators and Study Coordinators. Clinical evaluation of the CorCap cardiac support device in patients with dilated cardiomyopathy. Ann Thorac Surg. 2007;84:1226–1235. â•‡ 9. Gheorghiade M, Bonow RO. Chronic heart failure in the United States: a manifestation of coronary artery disease. Circulation. 1998;97:282–289. 10. American Heart Association. 2001 Heart and stroke statistical update. Dallas, TX: American Heart Association; 2000. 11. Vasan RS, Benjamin EJ, Levy D. Prevalence, clinical features and prognosis of diastolic heart failure: an epidemiologic study. J Am Coll Cardiol. 1995;26:1565–1574. 12. Vasan RS, Larsen MG, Benjamin EJ, et al. Congestive heart failure in subjects with normal versus reduced left ventricular ejection

17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

27. 28.

fraction: prevalence and mortality in a population based cohort. J Am Coll Cardiol. 1999;33:1948–1955. Levy D, Kenchaiah S, Larsen MG, et al. Long-term trends in the incidence of and survival with heart failure. N Engl J Med. 2002;347:1397–1402. Krumholz HM, Larson M, Levy D. Prognosis of left ventricular geometric patterns in the Framingham heart study. J Am Coll Cardiol. 1995;25:879–884. Gaasch WH, Delorey DE, St. John Sutton MG, Zile MR. Patterns of structural and functional remodeling of the left ventricle in chronic heart failure. Am J Cardiol. 2008;102:459–462. Nagueh SF, Appleton CP, Gillebert TC, et al. Recommendations for the evaluation of left ventricular diastolic function by echocardiography. J Am Soc Echocardiogr. 2009;22:107–133. St John Sutton M, Pfeffer MA, Moye LA, et al. Cardiovascular death and left ventricular remodeling two years after myocardial infarction: baseline predictors and impact of long-term use of Captopril: information from the survival and ventricular enlargement (SAVE) trial. Circulation. 1997;96:3294–3300. Gorman JH III, Gorman RC, Jackson BM, et al. Distortion of the mitral valve in acute ischemic mitral regurgitation. Ann Surg. 1997;64:1026–1031. Gorman JH III, Gorman RC, Plappert T, et al. Infarct size and location determine development of mitral regurgitation in the sheep model. J Thor Cardiovasc Surg. 1998;115(3):615–622. Ryan LP, Jackson BM, Parish LM, et al. Regional and global patterns of annular remodeling in ischemic mitral regurgitation. Ann Thorac Surg. 2007;84:553–559. Kramer CM, Lima JA, Reichek N, et al. Regional differences in function within non-infarcted myocardium during left ventricular remodeling. Circulation. 1993;88:1279–1288. Rumberger JA, Behrenbeck T, Breen JR, Reed JE, Gersh BJ. Nonparallel changes in global left ventricular chamber volume and muscle mass during the first year after transmural myocardial infarction in humans. J Am Coll Cardiol. 1993;21:673–682. Loh E, St. John Sutton MG, Wun CCC, et al. Ventricular dysfunction and the risk of stroke after myocardial infarction. N Engl J Med. 1997;336:251–257. Klein AL, Hatle LK, Taliercio CP, et al. Serial Doppler echocardiographic follow-up of left ventricular diastolic function in cardiac amyloidosis. J Am Coll Cardiol. 1990;16:1135–1141. Klein AL, Hatle LK, Taliercio CP, et al. Prognostic significance of Doppler measures of diastolic function in cardiac amyloidosis: a Doppler echocardiographic study. Circulation. 1991;83:808–816. Grigioni F, Enriquez-Sarano M, Zehr KJ, et al. Mitral regurgitation: long term outcome and prognostic implications with quantitative Doppler assessment. Circulation. 2001;103:1759–1764. Rapaport E. Natural history of aortic and mitral valve disease. Am J Cardiol. 1975;35:221–227. Ferrari VA, Scott CH, Holland GA, Axel L, St. John Sutton M. Three-dimensional contrast-enhanced magnetic resonance imaging and angiography in the diagnosis of partial anomalous pulmonary venous drainage. J Am Coll Cardiol. 2001;37:1120–1128.

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Multimodality Imaging in Hypertrophic Cardiomyopathy

DeBoraH H . KWon miLind Y. DeSai

Hypertrophic cardiomyopathy (HCM) is a complex Â�disorder with a broad phenotypic and morphologic spectrum. Furthermore, there is considerable heterogeneity in the clinical characteristics and natural history of HCM, with Â�clinical symptoms developing from infancy to greater than 90 years of age [1–6]. HCM is typically an autosomal dominant genetic cardiac disease with .12 identified genes thought to be responsible for this disorder [1,7–10]. It is one of the most common cardiac genetic disorders, with a prevalence of 1:500 in the general adult population [1,7–10]. Traditionally, the diagnosis of HCM has been primarily clinical, depending mostly on the use of echocardiography to evaluate for certain characteristic echocardiographic features such as left ventricular hypertrophy (LVH), asymmetric septal hypertrophy, and systolic anterior motion (SAM) of the mitral valve with left ventricular outflow tract (LVOT) obstruction. However, recently modalities such as cardiac magnetic resonance (CMR) and 3-dimensional (3D) echocardiography have demonstrated important potential utility in guiding the management of such a heterogeneous and often unpredictable disease.

jâ•… CLINICAL PRESENTATION While the phenotypic expression in HCM can vary greatly, most patients are asymptomatic and are incidentally diagnosed with this disease as the result of a murmur on physical examination, abnormal electrocardiogram, or unexplained LVH discovered on echocardiography. Symptomatic patients who experience adverse outcomes usually exhibit one or more of the following: (1) risk factors for sudden cardiac death (SCD), (2) progressive symptoms of exertional dyspnea and chest pain associated with presyncope or syncope in the setting of preserved LV function, (3) progressive congestive heart failure due to severe LV remodeling resulting in systolic dysfunction, and (4) supraventricular or ventricular arrhythmias and the potential adverse sequelae [1,7,11–13].

SCD is a catastrophic, but relatively common initial presentation in HCM patients [1,7,12,14,15]. SCD in this population is thought to be related to the development of complex ventricular tachyarrhythmias [7,16,17] often Â�during mild to moderate physical exertion. One study demonstrated that SCD tends to occur more often in the early morning hours [18]. While SCD is the most dreaded complication of HCM, it fortunately occurs in only a small fraction of HCM patients [1,6,7,19,20], and much effort has been devoted to identify this subset of patients who are at high risk. The currently identified risk factors for SCD include prior cardiac arrest, family history of SCD, unexplained syncope or near syncope, left ventricular thickness greater than 30 mm, a high-risk genetic mutation (eg, beta myosin heavychain mutations Arg403Gln and Arg719Gln), hypotensive response during exercise stress testing, and nonsustained VT on Holter monitoring [1,7,12,19,21–26]. Increased LVOT gradients, greater than 30 mm Hg, have also been shown to be associated with increased risk of SCD, progression to heart failure, and morbidity related to arrhythmia including stroke [27,28]. SCD has been shown to be exceedingly rare in patients without any of the previously mentioned risk factors (,3%) [19]. It is not yet clear if having multiple risk factors increases the risk of SCD in an additive fashion. Over the past 4 to 5 decades, our knowledge and understanding of HCM and its complex pathophysiology has been greatly expanded by the use of multimodality imaging. These modalities have been essential in selecting and guiding appropriate individual therapeutic strategies in HCM patients with varying degrees of symptoms and cardiac involvement. In this chapter, we explore the utility of current imaging methodologies and their applications in the diagnosis and treatment of patients with HCM.

jâ•… ECH OCARDIOGRAPH Y Assessment of Ventricular Morphology Echocardiography is the most commonly utilized diagnostic imaging modality to evaluate HCM. Echocardiography is capable of identifying the extent and characterization of LVH as well as LV dimensions and volumes. Asymmetric 12 7

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B

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D

F ig u re 9 . 1 â•…A symptomatic patient with a diagnosis of hypertrophic cardiomyopathy and typical severe septal hypertrophy. (A) Parasternal long-

axis view on surface echocardiography demonstrating severe basal septal hypertrophy. (B) Continuous-wave Doppler demonstrating a high dynamic gradient of 57 mm Hg through the left ventricular outflow tract following Valsalva maneuver. (C) Cardiac magnetic resonance (CMR) image of the 4-chamber steady-state free precession demonstrating severe septal hypertrophy during end-diastole. Note the very prominent anteroapically displaced papillary muscle. (D) DHE-CMR image in the same 4-chamber view demonstrating significant patchy scar in the severely hypertrophic septum.

upper septal hypertrophy is the most commonly observed morphologic pattern seen in HCM patients (Figure 9.1A) [29]. However, midventricular, apical (Figure 9.2A), posterolateral, and biventricular hypertrophy can also occur. Furthermore, approximately 5% of HCM patients have concentric LVH. Maximal wall thickness is calculated in the parasternal long-axis view and is an important measurement, as a thickness .30 mm is considered a risk factor for SCD in this population [20]. Therefore, an accurate measurement is imperative and care should be taken to avoid oblique transection of the septum by the ultrasound beam to exclude right ventricular myocardium on the right ventricular side. Also, the identification of the apical variant can be challenging with echocardiography as the endocardial borders may be difficult to identify in some patients, along with the possibility of apical fore-shortening. Quantification of LV mass should also

be performed using previously described semiquantitative scores [29,30]. More recently, real-time 3D echocardiography and CMR have been utilized to determine LV mass (Figures 9.1–9.3A). Role in Differential Diagnosis Other more common etiologies of LVH, such as hypertension or valvular disease, should be considered before conclusively diagnosing HCM. However, it may be Â�difficult to discern the presence of HCM in patients with mild concentric LVH, hypertension, and/or aortic stenosis. Recently, severely reduced systolic compression (by strain Doppler echocardiography) in the setting of asymmetric LVH readily identified biopsy-proven HCM patients from those with hypertension [31]. Genetic Â�testing and family history can often help to confirm the diagnosis of HCM.

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F ig u re 9 . 2 â•…An asymptomatic patient with a markedly abnormal electrocardiogram and a diagnosis of apical form of hypertrophic cardiomyopathy. (A) Three-dimensional echocardiogram in a 4-Â�chamber view demonstrating the apical variant. (B) Continuous-wave Doppler demonstrating a high dynamic gradient of 57 mm Hg through the left ventricular outflow tract (LVOT) following Valsalva maneuver. (C) LVOT view of a steady-state free precession cardiac magnetic resonance (CMR) image demonstrating severe apical hypertrophy. (D) DHE-CMR image in the same CMR view demonstrating significant patchy scar in the severely hypertrophic apex.

Distinguishing HCM from athlete’s heart is extremely important, as HCM patients engaging in competitive sports have a relatively high predisposition for SCD. The criteria for diagnosis of HCM in athletes differs from the normal population and is determined by the presence of wall thickness .12 mm (11 mm in women) in the presence of a nondilated LV [32]. This difference is because HCM patients usually have normal or reduced LV dimensions and no cavity dilatation (.55 mm is common in athletes), except with disease progression and systolic dysfunction. Also, HCM patients have abnormal myocardial mechanics, which can be detected by tissue Doppler (TD) imaging [33]. In borderline cases, it is reasonable to recommend the cessation of exercise with repeat imaging. Regression of physiologic LVH should occur in an athlete’s heart but not in pathologic LVH seen with HCM.

Evaluation of Systolic Function Hyperdynamic contractility is usually characteristic of HCM, whereas a small subset might develop LV enlargement along with LV systolic dysfunction. In HCM, a normal EF does not exclude contractile dysfunction, which can be detected by more sensitive techniques such as myocardial systolic velocities, strain rate, and strain [31,33]. Evaluation of Diastolic Function Due to the extensive hypertrophy and myocardial disarray, most HCM patients exhibit diastolic dysfunction. Several diastolic indices have been shown to be capable of estimating LV end diastolic pressure. Atrial flow signal recorded from the pulmonary veins [34] and tissue Doppler imaging

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A

B

C

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F ig u re 9 . 3 â•…A young patient with severe exertional dyspnea and syncope with dynamic left ventricular outflow tract (LVOT) obstruction without septal hypertrophy, due to abnormal papillary muscle morphology. (A) Surface echocardiogram in LVOT view demonstrating normal basal septal thickness during systole. Note the systolic anterior motion of the mitral valve. (B) Continuous-wave Doppler demonstrating a high dynamic gradient of 155 mm Hg through the LVOT following administration of amyl nitrite. (C) Cardiac magnetic resonance (CMR) image of the 4-chamber steady-state free precession during systole demonstrating normal septal hypertrophy. Note the abnormal double bifid papillary muscle which dragged the mitral apparatus closer to LVOT during systole resulting in LVOT obstruction. (D) DHE-CMR image in the same CMR view demonstrating no scar.

in combination with transmitral inflow can provide reasonably accurate predictions of filling pressures [34]. E-to-Ea ratio has been demonstrated to detect changes in filling pressures after alcohol-induced septal ablation [35,36] and cardiac surgery [36], and can predict exercise tolerance in both adults [37] as well as children [38] with HCM. In addition, septal Ea is an independent predictor of death and ventricular dysrhythmia in children with HCM [38]. Left atrial volume reflects the LA hemodynamic burden from LV diastolic dysfunction, mitral regurgitation (MR), and atrial myopathy. A number of studies have now reported a significant association between LA

dimensions and subsequent development of atrial fibrillation as well as adverse outcomes after myectomy [39]. However, cross-sectional studies have failed to significantly correlate Doppler filling patterns, extent of LVH, and invasive indexes of diastolic function [40]. In a recent study, we explored the relationship between segmental strains (using speckle tracking echocardiography) and myocardial fibrosis (using CMR) in HCM patients with preserved LV systolic fraction. Longitudinal, circumferential, and radial strains were found to be lower in HCM patients even in the absence of fibrosis. Myocardial fibrosis was associated with depressed longitudinal strain in HCM patients [41].

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Evaluation of LVOT Obstruction LVOT obstruction can occur at multiple levels in the same patient and is dynamic as the extent of obstruction varies with changes in heart rate, afterload, contractility, and intravascular volume [42]. The precise location of obstruction should be identified by careful placement of the pulse-wave Doppler. Continuous-wave Doppler is used to determine the peak LVOT gradient (Figures 9.1B, 9.2B, and 9.3B). Careful assessment of the Doppler envelope is necessary to identify if the MR jet is contaminating the measurement of the gradient across the LVOT. The mechanism of LVOT obstruction was traditionally thought to be due to the Venturi effect [29]. The Venturi theory proposes that the earliest event is an increased ejection velocity, leading to an increase in kinetic energy. The increase in kinetic energy is accompanied by a decrease in potential energy and local pressure, leading to the anterior motion of the mitral valve. This, in turn, leads to incomplete coaptation of the anterior and posterior mitral leaflets, resulting in MR (ie, eject, obstruct, leak sequence) [29]. However, recent studies have debunked this theory as SAM has been shown to occur even when the LVOT velocity is low [43]. According to some experts, SAM is now thought to be mainly due to drag forces [44] that act on the posterior surface of the anterior mitral valve leaflet and are proportional to the surface area of the leaflets exposed to these forces and systolic flow velocity. Regardless of the underlying mechanism, LVOT obstruction is associated with worse clinical outcomes, including progression to heart failure and death [27]. The use of Valsalva maneuver, amyl nitrite, exercise, and dobutamine can effectively result in a significant increase in LVOT obstruction. A significant change in LVOT velocity is easily acquired during the strain phase of Valsalva or with amyl nitrite in most patients. However, if the gradient still remains ,30 mm Hg, particularly in highly symptomatic patients, it is recommended to proceed to other methods of provoking obstruction. For those who are able to exercise, exercise stress echocardiography should be used [45]. If patients are unable or unwilling to exercise, medical provocation with dobutamine is a viable alternative. Isoproterenol has mainly been replaced by dobutamine injection in the echocardiography laboratory. Identifying and treating provocable obstruction has resulted in significant clinical, exercise, and hemodynamic improvement in HCM patients [46]. Evaluation of MR In HCM patients, MR is most often due to SAM and is posterolaterally directed. It can also occur in HCM patients due to myxomatous degeneration and less commonly because of rheumatic heart disease. The direction of the MR jet is an important clue in identifying the underlying mechanism [47], as an anteriorly/medially directed jet is most likely due to a primary leaflet pathology.

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Echocardiographic studies have demonstrated the reduced mobility and length of the posterior mitral leaflet, leading to a shorter coaptation length [48]. This results in a longer free segment of the anterior leaflet that is susceptible to drag forces, leading to SAM. However, septal myectomy usually effectively relieves the obstruction by widening the LVOT, resulting in diminished drag forces, and thus resolution of SAM and MR [49]. Facilitating Treatment Strategies Septal reduction via surgical myectomy or alcohol septal ablation has been shown to effectively improve LVOT obstruction. Intractably symptomatic patients, on maximally tolerated therapy, with dynamic obstruction at rest (.30 mm Hg) or provocation (.50 mm Hg) should be evaluated for definitive therapy. Surgical myectomy remains the most definitive treatment for such patients. Echocardiography plays a vital role in deciding definitive treatment for such patients. In particular, patients who have significant asymmetric upper septal hypertrophy and SAM will benefit the most from this therapy, which should generally be performed at a center with adequate surgical experience. However, septal reduction therapy will not improve obstruction in patients with intracavitary obstruction. Hence, conclusively establishing the exact site of obstruction using echocardiography is vital. Also, patients with coexisting valvular disease such as subvalvular fixed stenosis, anomalous insertion of a papillary muscle, or a flail mitral valve (diagnosed using echocardiography and/ or CMR) should be referred for open heart surgery for surgical correction. If septal reduction therapy cannot be performed due to inadequate septal thickness in the setting of significant LVOT obstruction, papillary muscle reorientation [50,51] or mitral valve repair/replacement may be alternative methods of relieving obstruction. In the experience of large centers with vast clinical HCM experience, patients should only be referred for percutaneous alcohol septal ablation if they are deemed to be at high risk for surgical septal myectomy [52,53]. Echocardiography During Alcohol Septal Reduction Myocardial contrast echocardiography provides essential procedural guidance and is routinely utilized during Â�alcohol septal reduction therapy [54]. Contrast echocardiography effectively identifies the myocardial territory that the septal perforator of interest supplies. Contrast opacification beyond the area of the basal anteroseptum, that is, inferior wall/RV segments or papillary muscle, precludes the injection of ethanol. Ethanol injection into these areas can result in incomplete LVOT obstruction relief and increased complications such as heart block. The reduction of LVOT gradient in the acute phase, which is monitored using transesophageal echocardiography, is related to the

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decrease in systolic Â�thickening and excursion of septal base due to necrosis/ischemia-Â�stunning as well as global decrease in LV systolic function [49]. The LVOT eventually ensues, resulting in a reduction in drag forces and peak LV ejection acceleration rate [49]. Echocardiography During Surgical Septal Myectomy Transesophageal echocardiography plays an invaluable role [55] at the time of septal myectomy by aiding in assessment of the amount of myocardium that should be removed. The thickness of the anteroseptum needs to be measured in multiple views, along with the length of myocardium between the aortic valve annulus and the site where the mitral valve approximates the myocardium during diastole. Midventricular obstruction, intrinsic mitral valve pathology, and anomalous papillary muscle insertion [56] should be identified by echocardiography and surgical inspection. Intraoperative transesophageal echocardiography is also important after myectomy to determine if residual SAM and LVOT obstruction is present. It can also determine if residual MR is present and if there is a need for further surgical correction. Furthermore, the effectiveness of septal resection should be determined after myectomy by assessing the LVOT obstruction with isoproterenol provocation. Inadequate septal resection is an important cause of residual obstruction and should be prevented with intraoperative echocardiographic guidance. In contrast to alcohol septal reduction therapy, the reduction in LVOT gradient after surgery occurs as a result of surgically widening of the LVOT, and is usually sustained indefinitely. Emerging Role of 3-Dimensional Echocardiography Several studies, evaluating the role and utility of 3D echocardiography in the evaluation of HCM patients, have been published recently. It has recently been shown to quantify and characterize myocardial hypertrophy (Figure 9.2A) and identify abnormal papillary muscle morphology, LV volumes, LVEF, and LV mass more accurately than traditional 2D echocardiography [57–59]. Furthermore, quantification of the LVOT area also has been shown to predict provocable LVOT gradients .50 mm Hg [60]. However, the incremental utility of 3D echocardiography has not yet been firmly established and is still limited to the academic research arena. Role in Screening and Evaluation of Asymptomatic HCM Currently, echocardiography remains the most practical technique at the present time for screening of HCM. It should be considered in first-degree relatives and potentially among other family members. In adolescents with asymptomatic HCM, annual repeat imaging is acceptable [61]. Repeat

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imaging is also reasonable in asymptomatic adults at longer time intervals of 5 years as LVH can develop later in life [61]. Myocardial Perfusion Scintigraphy Microvascular dysfunction is a recognized feature of HCM, likely due to dysplastic coronory arteries and severe LVH. Although HCM patients are not routinely referred for myocardial perfusion scintigraphy, a study demonstrated that the degree of microvascular dysfunction identified by dipyridamole positron emission tomography is a strong, independent predictor of worsening symptoms and death. In this study, severe microvascular dysfunction was not uncommon in patients with mild or no symptoms and preceded clinical deterioration by a few years [62].

jâ•… CARDIAC MAGNETIC RESONANCE Recent studies have demonstrated the increasing utility of CMR in the diagnosis and assessment of HCM. Because of persistent challenges in the noninvasive evaluation of HCM, better risk stratification of patients likely to benefit from effective but expensive therapies (including implantable defibrillators) with potential risks (device infection, inappropriate shocks) is required. CMR provides a more comprehensive assessment by providing the following advantages: ability to image in any plane; excellent visualization of epicardial and endocardial borders; consistent visualization of apex and inferior walls; accurate and precise assessment of overall dimensions, mass, function; and identification of myocardial fibrosis. Evaluation of Cardiac Morphology CMR can measure LV dimensions, volumes, and EF with excellent reproducibility [63], also in patients with LVH. Due to its 3D capabilities, CMR is especially useful in the identification of atypical forms of HCM, including those involving the anterolateral free wall [64] and apical variant [65], which might not be visualized with echocardiography due to the limited imaging windows (Figures 9.1C, 9.2C, and 9.3C). Recently, a relatively high prevalence of apical aneurysms and its clinical significance, which have thus far been underappreciated, was demonstrated using CMR [66]. Quantification of LV mass by CMR is thus more accurate and has recently been shown to be correlated with adverse outcomes in HCM patients [67]. With the added ability of delayed enhancement sequences to identify and characterize myocardial scar, CMR is proving to be a vital adjunct to echocardiography, when evaluating patients with abnormal Q waves and/or anterolateral T-wave abnormalities and no obvious underlying etiology ( Figures 9.1D, 9.2D, and 9.3D). CMR might also potentially be useful for familial screening and genetic linkage studies.

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CMR is now considered a class I indication for patients with apical HCM (Figure 9.2C and D) and a class II indication for other phenotypic variants of HCM (Figure 9.1C and D) [63]. Furthermore, CMR has been utilized to further assess papillary muscle morphology in HCM patients [68,69]. Several studies have shown that mitral valve apparatus abnormalities, such as leaflet elongation [70], anteriorly displaced coaptation of the mitral valve leaflets [43,71–73], as well as abnormal papillary muscle morphology [74–77], may be associated with increased LVOT obstruction, independent of septal thickness [78–80]. Two recent studies have demonstrated that HCM patients had a high frequency of papillary Â�muscle abnormalities (anteroapical displacement and/or double bifid/multiple accessory papillary muscles) (Figures 9.1C and 9.3C) [68,69]. The papillary muscle and septal thickness were higher in HCM patients as compared to normal patients, resulting in significantly reduced distance between anterolateral papillary muscle and septum, and effectively reducing the LV cavity volume. In the study by Kwon et al abnormal papillary muscle morphology (anteroapical displacement of the anterolateral papillary muscle and double bifid papillary muscle) was associated with increased prevalence of SAM and higher resting LVOT gradients; and this association was independent of septal thickness. Also, the odds of having an abnormal resting LVOT gradient were significantly higher in those HCM patients with anteroapically displaced anterolateral papillary muscle or double bifid papillary muscles, independent of septal thickness. Furthermore, of the HCM patients with abnormal papillary morphology who underwent septal myectomy (without repositioning of papillary muscles), 23% had a residual provocable LVOT gradient. Clinical utility of CMR is increasing with the recognition that a subset of patients with dynamic LVOT obstruction have normal LV thickness; and the only abnormality noted involves abnormal orientation of papillary muscles [81]. A recent case report described a highly symptomatic patient with normal septal thickness but a significant LVOT gradient. This patient tested positive for a mutation (459delC) in the myosin-binding protein C (MYPBC3) gene and was noted to have multiple papillary muscles heads on CMR, which obstructed the LVOT during systole. The patient underwent papillary muscle reorientation, which resolved his LVOT gradient [50,51]. Therefore, surgical correction of abnormal papillary muscles (either by reorientation [51] or by resection) may provide incremental value to septal myectomy/mitral valve repair alone. CMR is becoming the test of choice because of its ability to precisely evaluate papillary muscle morphology and orientation. Evaluation of Regional Function and Flow Characteristics CMR studies have demonstrated blunted circumferential shortening in hypertrophied segments and inverse relation

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to local thickness with most shortening occurring in early systole was also found [82,83]. Longitudinal shortening is likewise reduced in the basal septum [83]. On a global basis, the number of hypokinetic segments is a strong independent predictor of LV mass, confirming the association of LVH with myocardial dysfunction [84]. In patients with LVOT obstruction, phase velocity flow mapping (both in-pane and through-plane) is useful to determine the peak velocity in a manner similar to Doppler echocardiography. In a study to assess the relation of the pressure gradient as assessed by TTE and the CMR-derived planimetry of LVOT, a cutoff value of 2.7 cm2 identified obstruction as defined by TTE with 100% accuracy [85]. Phase-contrast velocity mapping also aids in calculation of MR fraction. Evaluation of Myocardial Fibrosis A unique advantage of CMR is the added ability to identify myocardial fibrosis using the delayed hyperenhancement technique (Figures 9.1D and 9.2D). In patients with HCM, the characteristic pattern of myocardial fibrosis is distinct, as compared to other disease patterns. Typically, the fibrosis is patchy, midwall, with multiple foci and most commonly found in regions of hypertrophy. However, a wide array of patterns can be seen, including a diffuse trans-septal or RV insertion septal pattern, a more confluent pattern that is transmural, or a patchy, multifocal pattern. The pattern, distribution, and amount of fibrosis as determined by delayed-enhanced CMR in HCM patients correlate closely with histopathology in explanted hearts of patients undergoing cardiac transplantation [86]. The mechanism for development of scarring has not been entirely elucidated, but may reflect microvascular ischemia due to various factors. A study by Maron et al [87] suggested that myocardial scarring was a result of ischemia as areas of scarring were found to be correlated to areas of abnormal intramural coronary arteries. Ischemia due to severe LVH may also contribute to myocardial fibrosis. Choudhury et al demonstrated that myocardial replacement fibrosis was detectable in more than 80% of asymptomatic HCM patients, and correlated with wall thickness and inversely with regional function [88]. In a study of 68 HCM patients, with preserved LVEF, Kwon et al demonstrated a strong association between LV thickness and degree of myocardial fibrosis [89]. In a prospective cohort of HCM patients with known troponin I mutations, 80% of patients with underlying LVH demonstrated late enhancement [90]. Teraoka et al reported that myocardial fibrosis was observed in 75% of patients with HCM, typically small and patchy, and mostly distributed in the interventricular septum [91]. The clinical significance of fibrosis is still uncertain. Current data indicate that the extent of myocardial fibrosis particularly in younger patients (,40 years) is associated with clinical markers of SCD (21% with .2 risk factors). In older patients, over 40 years, fibrosis may be

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A

B

Figure 9.4â•…A patient with a diagnosis of Fabry’s disease. (A) DHE–cardiac magnetic resonance (CMR) image demonstrating mild scar in the

characteristic posterobasal location. (B) CMR image of the 4-chamber steady-state free precession during end-diastole demonstrating concentric LV hypertrophy.

associated with a greater likelihood for progressive disease. Furthermore, Kwon et al and Adabag et al demonstrated an association between degree of myocardial fibrosis and ventricular arrhythmia noted on Holter monitoring [89,92]. In the study by Teraoka et al the extent and presence of fibrosis correlated directly with the development of ventricular arrhythmias [91] and as such may help aid in risk stratification of HCM patients at higher risk of SCD and those that may need ICD implantation over and beyond current risk stratification algorithms. Evaluation of the Success of Treatment Following alcohol septal ablation, CMR can aid in early and midterm LV remodeling based on the size and location of the induced infarct. One study demonstrated that myocardial hypertrophy is, at least in part, afterload dependent, reversible, and not caused exclusively by the genetic disorder [93]. In a study of 10 patients who underwent alcohol septal ablation, CMR demonstrated a continuous and nonlinear improvement of the outflow tract area during a 12-month period of follow-up, which correlated well with symptomatic improvement [94]. However, a study by Valeti et al utilized CMR to demonstrate the unpredictability of percutaneous alcohol septal ablation when compared to surgical septal myectomy [95]. With septal myectomy, the discrete area of resected tissue was consistently localized to the anterior septum. However, with alcohol septal ablation, the location of ablation varied and was more commonly located more inferiorly in the basal septum and extended into the right ventricular side of the septum. Several patients in

the percutaneous patient group had residual LVOT gradients and ablations that were entirely outside the basal septum. Role in Differential Diagnosis CMR has a similar utility as echocardiography in the differential diagnosis of HCM (eg, hypertension, aortic stenosis, and athlete’s heart). Furthermore, CMR can be particularly useful if echocardiography is suboptimal or inconclusive. CMR can also differentiate HCM from infiltrative diseases. About 5% of patients with phenotypes of HCM will have Fabry’s disease, which is an X-linked recessive glycolipid storage disease characterized by deficient -galactosidase activity (Figure 9.4). Delayed hyperenhancement studies in these patients demonstrate a predilection for midwall fibrosis of the basal lateral wall unlike HCM (Figure 9.4A). The pattern of hypertrophy is usually more concentric than that in HCM (Figure 9.4B) [86]. Amyloidosis has a characteristic hyperenhancement pattern on delayed CMR images [96].

jâ•… CON CL USIO NS In summary, HCM is a heterogeneous disease with complex morphologic characteristics that can be accurately diagnosed and appropriately treated utilizing a multimodality imaging approach. Furthermore, these different imaging studies can play a critical role in risk stratification for SCD when applied in addition to the patient’s clinical history.

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jâ•… REFERENCES â•‡ 1. Maron BJ. Hypertrophic cardiomyopathy: a systematic review. JAMA. 2002;287:1308–1320. â•‡ 2. Braunwald E, Lambrew CT, Rockoff SD, Ross J Jr, Morrow AG. Idiopathic hypertrophic subaortic stenosis I. A description of the Â�disease based upon an analysis of 64 patients. Circulation. 1964;30 (suppl 4):3–119. â•‡ 3. Maron BJ, Spirito P. Impact of patient selection biases on the perception of hypertrophic cardiomyopathy and its natural history. Am J Cardiol. 1993;72:970–972. â•‡ 4. Maron BJ, Casey SA, Poliac LC, Gohman TE, Almquist AK, Aeppli DM. Clinical course of hypertrophic cardiomyopathy in a regional United States cohort. JAMA. 1999;281:650–655. â•‡ 5. Spirito P, Chiarella F, Carratino L, Berisso MZ, Bellotti P, Vecchio C. Clinical course and prognosis of hypertrophic cardiomyopathy in an outpatient population. N Engl J Med. 1989;320:749–755. â•‡ 6. Elliott P. Relation between the severity of left ventricular hypertrophy and prognosis in patients with hypertrophic cardiomyopathy. Lancet. 2001;357:420–424. â•‡ 7. Maron BJ, MWea. ACC/ESC expert consensus document on hypertrophic cardiomyopathy. J Am Coll Cardiol. 2003;42. â•‡ 8. Ho CY, Seidman CE. A contemporary approach to hypertrophic cardiomyopathy. Circulation. 2006;113:e858–e862. â•‡ 9. Maron BJ, Moller JH, Seidman CE, et al. Impact of laboratory molecular diagnosis on contemporary diagnostic criteria for genetically transmitted cardiovascular diseases: hypertrophic cardiomyopathy, long-QT syndrome, and Marfan syndrome. [A statement for healthcare professionals from the Councils on Clinical Cardiology, Cardiovascular Disease in the Young, and Basic Science, American Heart Association]. Circulation. 1998;98:1460–1471. 10. Richard P, Charron P, Carrier L, et al. Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. Circulation. 2003;107:2227–2232. 11. Maron BJ. Hypertrophic cardiomyopathy. Lancet. 1997;350:127–133. 12. Spirito P. The management of hypertrophic cardiomyopathy. N Engl J Med. 1997;336:775–785. 13. Maron BJ. Clinical profile of stroke in 900 patients with hypertrophic cardiomyopathy. J Am Coll Cardiol. 2002;39:301–307. 14. Elliott P, McKenna WJ. Hypertrophic cardiomyopathy. Lancet. 2004;363:1881–1891. 15. Spirito P, Autore C. Management of hypertrophic cardiomyopathy. BMJ. 2006;332:1251–1255. 16. Elliott PM, Sharma S, Varnava A, Poloniecki J, Rowland E, McKenna WJ. Survival after cardiac arrest or sustained ventricular tachycardia in patients with hypertrophic cardiomyopathy. J Am Coll Cardiol. 1999;33:1596–1601. 17. Maron BJ, Shen WK, Link MS, et al. Efficacy of implantable cardioverter-defibrillators for the prevention of sudden death in patients with hypertrophic cardiomyopathy. N Engl J Med. 2000;342:365–373. 18. Maron BJ, Kogan J, Proschan MA, Hecht GM, Roberts WC. Circadian variability in the occurrence of sudden cardiac death in patients with hypertrophic cardiomyopathy. J Am Coll Cardiol. 1994;23:1405–1409. 19. Elliott PM, Poloniecki J, Dickie S, et al. Sudden death in hypertrophic cardiomyopathy: identification of high risk patients. J Am Coll Cardiol. 2000;36:2212–2218. 20. Spirito P, Bellone P, Harris KM, Bernabo P, Bruzzi P, Maron BJ. Magnitude of left ventricular hypertrophy and risk of sudden death in hypertrophic cardiomyopathy. N Engl J Med. 2000;342:1778–1785. 21. Monserrat L, Elliott PM, Gimeno JR, Sharma S, Penas-Lado M, McKenna WJ. Non-sustained ventricular tachycardia in hypertrophic cardiomyopathy: an independent marker of sudden death risk in young patients. J Am Coll Cardiol. 2003;42:873–879. 22. Yoshida N, Ikeda H, Wada T, et al. Exercise-induced abnormal blood pressure responses are related to subendocardial ischemia in hypertrophic cardiomyopathy. J Am Coll Cardiol. 1998;32:1938–1942.

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23. Olivotto I, Cecchi F, Casey SA, Dolara A, Traverse JH, Maron BJ. Impact of atrial fibrillation on the clinical course of hypertrophic cardiomyopathy. Circulation. 2001;104:2517–2524. 24. Cecchi F, Olivotto I, Montereggi A, Squillatini G, Dolara A, Maron BJ. Prognostic value of non-sustained ventricular tachycardia and the potential role of amiodarone treatment in hypertrophic cardiomyopathy: assessment in an unselected non-referral based patient population. Heart. 1998;79:331–336. 25. Moolman JC, Corfield VA, Posen B, et al. Sudden death due to troponin T mutations. J Am Coll Cardiol. 1997;29:549–555. 26. Watkins H. Sudden death in hypertrophic cardiomyopathy. N Engl J Med. 2000;342:422–424. 27. Maron MS, Olivotto I, Betocchi S, et al. Effect of left ventricular outflow tract obstruction on clinical outcome in hypertrophic cardiomyopathy. N Engl J Med. 2003;348:295–303. 28. Kofflard MJ, Ten Cate FJ, van der Lee C, van Domburg RT. Hypertrophic cardiomyopathy in a large community-based population: clinical outcome and identification of risk factors for sudden cardiac death and clinical deterioration. J Am Coll Cardiol. 2003;41:987–993. 29. Wigle ED, Sasson Z, Henderson MA, et al. Hypertrophic cardiomyopathy. The importance of the site and the extent of hypertrophy. A review. Prog Cardiovasc Dis. 1985;28:1–83. 30. Spirito P, Maron BJ. Relation between extent of left ventricular hypertrophy and occurrence of sudden cardiac death in hypertrophic cardiomyopathy. J Am Coll Cardiol. 1990;15:1521–1526. 31. Kato TS, Noda A, Izawa H, et al. Discrimination of nonobstructive hypertrophic cardiomyopathy from hypertensive left ventricular hypertrophy on the basis of strain rate imaging by tissue Doppler ultrasonography. Circulation. 2004;110:3808–3814. 32. Sharma S, Maron BJ, Whyte G, Firoozi S, Elliott PM, McKenna WJ. Physiologic limits of left ventricular hypertrophy in elite junior athletes: relevance to differential diagnosis of athlete’s heart and hypertrophic cardiomyopathy. J Am Coll Cardiol. 2002;40:1431–1436. 33. Rajiv C, Vinereanu D, Fraser AG. Tissue Doppler imaging for the evaluation of patients with hypertrophic cardiomyopathy. Curr Opin Cardiol. 2004;19:430–436. 34. Nagueh SF, Lakkis NM, Middleton KJ, Spencer WH 3rd, Zoghbi WA, Quinones MA. Doppler estimation of left ventricular filling pressures in patients with hypertrophic cardiomyopathy. Circulation. 1999;99:254–261. 35. Nagueh SF, Lakkis NM, Middleton KJ, et al. Changes in left ventricular filling and left atrial function six months after nonsurgical septal reduction therapy for hypertrophic obstructive cardiomyopathy. J Am Coll Cardiol. 1999;34:1123–1128. 36. Sitges M, Shiota T, Lever HM, et al. Comparison of left ventricular diastolic function in obstructive hypertrophic cardiomyopathy in patients undergoing percutaneous septal alcohol ablation versus surgical myotomy/myectomy. Am J Cardiol. 2003;91:817–821. 37. Matsumura Y, Elliott PM, Virdee MS, Sorajja P, Doi Y, McKenna WJ. Left ventricular diastolic function assessed using Doppler tissue imaging in patients with hypertrophic cardiomyopathy: relation to symptoms and exercise capacity. Heart. 2002;87:247–251. 38. McMahon CJ, Nagueh SF, Pignatelli RH, et al. Characterization of left ventricular diastolic function by tissue Doppler imaging and clinical status in children with hypertrophic cardiomyopathy. Circulation. 2004;109:1756–1762. 39. Woo A, Williams WG, Choi R, et al. Clinical and echocardiographic determinants of long-term survival after surgical myectomy in obstructive hypertrophic cardiomyopathy. Circulation. 2005;111:2033–2041. 40. Nishimura RA, Appleton CP, Redfield MM, Ilstrup DM, Holmes DR Jr, Tajik AJ. Noninvasive Doppler echocardiographic evaluation of left ventricular filling pressures in patients with cardiomyopathies: a simultaneous Doppler echocardiographic and cardiac catheterization study. J Am Coll Cardiol. 1996;28:1226–1233. 41. Popovic ZB, Kwon DH, Mishra M, et al. Association between regional ventricular function and myocardial fibrosis in hypertrophic cardiomyopathy assessed by speckle tracking echocardiography and delayed hyperenhancement magnetic resonance imaging. J Am Soc Echocardiogr. 2008;21:1299–1305.

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42. Maron BJ, McKenna WJ, Danielson GK, et al. American College of Cardiology/European Society of Cardiology Clinical Expert Consensus Document on Hypertrophic Cardiomyopathy. A report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents and the European Society of Cardiology Committee for Practice Guidelines. Eur Heart J. 2003;24:1965–1991. 43. Sherrid MV, Gunsburg DZ, Moldenhauer S, Pearle G. Systolic anterior motion begins at low left ventricular outflow tract velocity in obstructive hypertrophic cardiomyopathy. J Am Coll Cardiol. 2000;36:1344–1354. 44. Sherrid MV, Chu CK, Delia E, Mogtader A, Dwyer EM Jr. An echocardiographic study of the fluid mechanics of obstruction in hypertrophic cardiomyopathy. J Am Coll Cardiol. 1993;22:816–825. 45. Maron BJ, McKenna WJ, Danielson GK, et al. American College of Cardiology/European Society of Cardiology clinical expert consensus document on hypertrophic cardiomyopathy. A report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents and the European Society of Cardiology Committee for Practice Guidelines. J Am Coll Cardiol. 2003;42:1687–1713. 46. Lakkis N, Plana JC, Nagueh S, Killip D, Roberts R, Spencer WH 3rd. Efficacy of nonsurgical septal reduction therapy in symptomatic patients with obstructive hypertrophic cardiomyopathy and provocable gradients. Am J Cardiol. 2001;88:583–586. 47. Yu EH, Omran AS, Wigle ED, Williams WG, Siu SC, Rakowski H. Mitral regurgitation in hypertrophic obstructive cardiomyopathy: relationship to obstruction and relief with myectomy. J Am Coll Cardiol. 2000;36:2219–2225. 48. Schwammenthal E, Nakatani S, He S, et al. Mechanism of mitral regurgitation in hypertrophic cardiomyopathy: mismatch of posterior to anterior leaflet length and mobility. Circulation. 1998;98:856–865. 49. Flores-Ramirez R, Lakkis NM, Middleton KJ, Killip D, Spencer WH 3rd, Nagueh SF. Echocardiographic insights into the mechanisms of relief of left ventricular outflow tract obstruction after nonsurgical septal reduction therapy in patients with hypertrophic obstructive cardiomyopathy. J Am Coll Cardiol. 2001;37:208–214. 50. Austin BA, Kwon DH, Smedira NG, Thamilarasan M, Lever HM, Desai MY. Abnormally thickened papillary muscle resulting in dynamic left ventricular outflow tract obstruction: an unusual presentation of hypertrophic cardiomyopathy. J Am Soc Echocardiogr. In press. 51. Bryant R 3rd, Smedira NG. Papillary muscle realignment for symptomatic left ventricular outflow tract obstruction. J Thorac Cardiovasc Surg. 2008;135:223–224. 52. Kwon DH, Kapadia SR, Tuzcu EM, et al. Long-term outcomes in high risk symptomatic patients with hypertrophic cardiomyopathy undergoing alcohol septal ablation. JACC Cardiovasc Interv. 2008;1:432–438. 53. Sorajja P, Valeti U, Nishimura RA, et al. Outcome of alcohol septal ablation for obstructive hypertrophic cardiomyopathy. Circulation. 2008;118:131–139. 54. Nagueh SF, Lakkis NM, He ZX, et al. Role of myocardial contrast echocardiography during nonsurgical septal reduction therapy for hypertrophic obstructive cardiomyopathy. J Am Coll Cardiol. 1998;32:225–229. 55. Ommen SR, Park SH, Click RL, Freeman WK, Schaff HV, Tajik AJ. Impact of intraoperative transesophageal echocardiography in the surgical management of hypertrophic cardiomyopathy. Am J Cardiol. 2002;90:1022–1024. 56. Minakata K, Dearani JA, Schaff HV, O’Leary PW, Ommen SR, Danielson GK. Mechanisms for recurrent left ventricular outflow tract obstruction after septal myectomy for obstructive hypertrophic cardiomyopathy. Ann Thorac Surg. 2005;80:851–856. 57. Bicudo LS, Tsutsui JM, Shiozaki A, et al. Value of real time threedimensional echocardiography in patients with hypertrophic cardiomyopathy: comparison with two-dimensional echocardiography and magnetic resonance imaging. Echocardiography. 2008;25:717–726.

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58. Caselli S, Pelliccia A, Maron M, et al. Differentiation of hypertrophic cardiomyopathy from other forms of left ventricular hypertrophy by means of three-dimensional echocardiography. Am J Cardiol. 2008;102:616–620. 59. Yang HS, Lee KS, Chaliki HP, et al. Anomalous insertion of the papillary muscle causing left ventricular outflow obstruction: visualization by real-time three-dimensional echocardiography. Eur J Echocardiogr. 2008;9:855–860. 60. Fukuda S, Lever HM, Stewart WJ, et al. Diagnostic value of left ventricular outflow area in patients with hypertrophic cardiomyopathy: a real-time three-dimensional echocardiographic study. J Am Soc Echocardiogr. 2008;21:789–795. 61. Maron BJ, Seidman JG, Seidman CE. Proposal for contemporary screening strategies in families with hypertrophic cardiomyopathy. J Am Coll Cardiol. 2004;44:2125–2132. 62. Cecchi F, Olivotto I, Gistri R, Lorenzoni R, Chiriatti G, Camici PG. Coronary microvascular dysfunction and prognosis in hypertrophic cardiomyopathy. N Engl J Med. 2003;349:1027–1035. 63. Pennell DJ, Sechtem UP, Higgins CB, et al. Clinical indications for cardiovascular magnetic resonance (CMR): Consensus Panel report. J Cardiovasc Magn Reson. 2004;6:727–765. 64. Rickers C, Wilke NM, Jerosch-Herold M, et al. Utility of cardiac magnetic resonance imaging in the diagnosis of hypertrophic cardiomyopathy. Circulation. 2005;112:855–861. 65. Moon JC, Fisher NG, McKenna WJ, Pennell DJ. Detection of apical hypertrophic cardiomyopathy by cardiovascular magnetic resonance in patients with non-diagnostic echocardiography. Heart. 2004;90:645–649. 66. Maron MS, Finley JJ, Bos JM, et al. Prevalence, clinical significance, and natural history of left ventricular apical aneurysms in hypertrophic cardiomyopathy. Circulation. 2008;118:1541–1549. 67. Olivotto I, Maron MS, Autore C, et al. Assessment and significance of left ventricular mass by cardiovascular magnetic resonance in hypertrophic cardiomyopathy. J Am Coll Cardiol. 2008;52:559–566. 68. Kwon DH, Setser RM, Thamilarasan M, et al. Abnormal papillary muscle morphology is independently associated with increased left ventricular outflow tract obstruction in hypertrophic cardiomyopathy. Heart. 2008;94:1295–1301. 69. Harrigan CJ, Appelbaum E, Maron BJ, et al. Significance of papillary muscle abnormalities identified by cardiovascular magnetic resonance in hypertrophic cardiomyopathy. Am J Cardiol. 2008;101:668–673. 70. O’Connor M, Wolstenholme GEW, eds. Hypertrophic Obstructive Cardiomyopathy. London, England: Churchill; 1971:220 p. 71. Klues HG, Maron BJ, Dollar AL, Roberts WC. Diversity of structural mitral valve alterations in hypertrophic cardiomyopathy. Circulation. 1992;85:1651–1660. 72. Klues HG, Roberts WC, Maron BJ. Morphological determinants of echocardiographic patterns of mitral valve systolic anterior motion in obstructive hypertrophic cardiomyopathy. Circulation. 1993;87:1570–1579. 73. Krasnow N. An acquired disease component in hypertrophic cardiomyopathy: new clinical clarifications. J Am Coll Cardiol. 1989;13:46–47. 74. Henry WL, Clark CE, Griffith JM, Epstein SE. Mechanism of left ventricular outflow obstruction in patients with obstructive asymmetric septal hypertrophy (idiopathic hypertrophic subaortic stenosis). Am J Cardiol. 1975;35:337–345. 75. Reis RL, Bolton MR, King JF, Pugh DM, Dunn MI, Mason DT. Anterior-superior displacement of papillary muscles producing obstruction and mitral regurgitation in idiopathic hypertrophic subaortic stenosis. Operative relief by posterior-superior realignment of papillary muscles following ventricular septal myectomy. Circulation. 1974;50(suppl 2):II181–II188. 76. Kon MW, Grech ED, Ho SY, Bennett JG, Collins PD. Anomalous papillary muscle as a cause of left ventricular outflow tract obstruction in an adult. Ann Thorac Surg. 1997;63:232–234. 77. Klues HG, Roberts WC, Maron BJ. Anomalous insertion of Â�papillary muscle directly into anterior mitral leaflet in hypertrophic

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Â� cardiomyopathy. Significance in producing left ventricular outflow obstruction. Circulation. 1991;84:1188–1197. 78. Galler M, Kronzon I, Slater J, et al. Long-term follow-up after mitral valve reconstruction: incidence of postoperative left ventricular outflow obstruction. Circulation. 1986;74(suppl 1):I99–I103. 79. Schiavone WA, Cosgrove DM, Lever HM, Stewart WJ, Salcedo EE. Long-term follow-up of patients with left ventricular outflow tract obstruction after Carpentier ring mitral valvuloplasty. Circulation. 1988;78(suppl 1):I60–I65. 80. Maron BJ, Epstein SE, Bonow RO, Wyngaarden MK, Wesley YE. Obstructive hypertrophic cardiomyopathy associated with minimal left ventricular hypertrophy. Am J Cardiol. 1984;53:377–379. 81. Kwon D, Setser R, Thamilarasan M, et al. Abnormal papillary muscle morphology is independently associated with increased left ventricular outflow tract obstruction in hypertrophic cardiomyopathy. Heart. 2007. 82. Dong SJ, MacGregor JH, Crawley AP, et al. Left ventricular wall thickness and regional systolic function in patients with hypertrophic cardiomyopathy. A three-dimensional tagged magnetic resonance imaging study. Circulation. 1994;90:1200–1209. 83. Kramer CM, Reichek N, Ferrari VA, Theobald T, Dawson J, Axel L. Regional heterogeneity of function in hypertrophic cardiomyopathy. Circulation. 1994;90:186–194. 84. Sipola P, Lauerma K, Jaaskelainen P, et al. Cine MR imaging of myocardial contractile impairment in patients with hypertrophic cardiomyopathy attributable to Asp175Asn mutation in the alphatropomyosin gene. Radiology. 2005;236:815–824. 85. Schulz-Menger J, Abdel-Aty H, Busjahn A, et al. Left ventricular outflow tract planimetry by cardiovascular magnetic resonance differentiates obstructive from non-obstructive hypertrophic cardiomyopathy. J Cardiovasc Magn Reson. 2006;8:741–746. 86. Moon JC, Sheppard M, Reed E, Lee P, Elliott PM, Pennell DJ. The histological basis of late gadolinium enhancement cardiovascular magnetic resonance in a patient with Anderson-Fabry disease. J Cardiovasc Magn Reson. 2006;8:479–482.

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87. Maron BJ, Wolfson JK, Epstein SE, Roberts WC. Intramural (“small vessel”) coronary artery disease in hypertrophic cardiomyopathy. J Am Coll Cardiol. 1986;8:545–557. 88. Choudhury L, Mahrholdt H, Wagner A, et al. Myocardial scarring in asymptomatic or mildly symptomatic patients with hypertrophic cardiomyopathy. J Am Coll Cardiol. 2002;40:2156–2164. 89. Kwon DH, Setser RM, Popovic ZB, et al. Association of myocardial fibrosis, electrocardiography and ventricular tachyarrhythmia in hypertrophic cardiomyopathy: a delayed contrast enhanced MRI study [published online ahead of print January 19, 2008]. Int J Cardiovasc Imaging. 90. Moon JC, Mogensen J, Elliott PM, et al. Myocardial late gadolinium enhancement cardiovascular magnetic resonance in hypertrophic cardiomyopathy caused by mutations in troponin I. Heart. 2005;91:1036–1040. 91. Teraoka K, Hirano M, Ookubo H, et al. Delayed contrast enhancement of MRI in hypertrophic cardiomyopathy. Magn Reson Imaging. 2004;22:155–161. 92. Adabag AS, Maron BJ, Appelbaum E, et al. Occurrence and frequency of arrhythmias in hypertrophic cardiomyopathy in relation to delayed enhancement on cardiovascular magnetic resonance. J Am Coll Cardiol. 2008;51:1369–1374. 93. van Dockum WG, Beek AM, ten Cate FJ, et al. Early onset and progression of left ventricular remodeling after alcohol septal ablation in hypertrophic obstructive cardiomyopathy. Circulation. 2005;111:2503–2508. 94. Schulz-Menger J, Strohm O, Waigand J, Uhlich F, Dietz R, Friedrich MG. The value of magnetic resonance imaging of the left ventricular outflow tract in patients with hypertrophic obstructive cardiomyopathy after septal artery embolization. Circulation. 2000;101:1764–1766. 95. Valeti US, Nishimura RA, Holmes DR, et al. Comparison of surgical septal myectomy and alcohol septal ablation with cardiac magnetic resonance imaging in patients with hypertrophic obstructive cardiomyopathy. J Am Coll Cardiol. 2007;49:350–357. 96. Maceira AM, Joshi J, Prasad SK, et al. Cardiovascular magnetic resonance in cardiac amyloidosis. Circulation. 2005;111:186–193.

10

Chronic Myocardial Ischemia and Viability

Caroline A . Daly O tavio R . Coelho-Filho Raymon d Y. K wong

The identification of myocardial ischemia and the assessment of viability have been areas of major interest in cardiology for more than 60 years, but even more considerably so with the dramatic expansion of cardiovascular imaging in recent times. Assessment of ischemia has been widely performed since the 1940s, through the use of exercise echocardiography (ECG) [1] followed by the development of nuclear cardiology techniques, stress ECG, and more recently cardiac magnetic resonance imaging. The importance of viability assessment has grown from initial observations made during early studies of surgical revascularization, which showed ventricular function recovery in a significant proportion of patients with impaired left ventricular (LV) function after revascularization [2]. Assessment of viability now encompasses a wide range of techniques from thallium or technetium tracer single photon emission computed tomography studies, to positron emission tomography (PET) using single or dual isotopes, stress ECG, or cardiac magnetic resonance imaging. This chapter will describe and compare these imaging modalities with an emphasis on the growing bank of clinical data supporting newer techniques such as cardiovascular magnetic resonance (CMR), clinical settings where imaging may be used to the greatest advantage, and comment on future directions in cardiovascular imaging of chronic ischemia and viability.

jâ•…I SC HEMIA, VIABILITY, AND HIBERNATION To begin, a brief description of the pathophysiological processes themselves may be useful. Put most simply, myocardial ischemia is an imbalance between oxygen consumption and oxygen supply at cellular level. A more complete definition would include the fact that ischemia 13 8

occurs when myocardial oxygen deprivation is accompanied by inadequate removal of metabolites because of reduced blood flow or perfusion, differentiating it from hypoxia related to reduced oxygen supply with adequate perfusion as encountered in severe anemia, cyanotic congenital heart disease, cor pulmonale, or carbon monoxide poisoning. Oxygen consumption is driven by metabolic demands that are affected by many factors including heart rate (HR), contractility, systolic wall tension, maintenance of cell viability in basal state, depolarization, activation, maintenance of active state, direct metabolic effect of catecholamines, and fatty acid uptake. In the normal heart, coronary blood flow is controlled by a complex and elegant process of autoregulation, which involves rapid alteration in coronary vascular resistance in response to myocardial oxygen demand, predominantly at the arteriolar level. This process, achieved through a combination of endothelial function and myogenic control, can effectively increase coronary blood flow by a factor of 3 to 5 in response to increased myocardial work, as occurs during physical exertion in normal individuals. In patients with coronary stenosis, autoregulatory dilation of the resistance vessels compensates for reductions in perfusion pressure distal to the stenosis. In studies that have compared perfusion pressure distal to coronary stenoses as measured by pressure wire and myocardial perfusion in the same territory as assessed by PET, myocardial perfusion has been shown to remain relatively constant over a pressure range of 45 to 125 mm Hg. Thus, tissue perfusion distal to the stenosis is usually adequate at rest; however, with increased demand, epicardial blood flow is limited by the stensosis [3]. Distal perfusion is compromised as the pressure distal to the stenosis diminishes further and demand ischemia ensues. Although the most important determinant of stenosis resistance is the minimum diameter of the stenosis (the trans-stenotic pressure drop is inversely proportional to the fourth power of the minimum luminal diameter), it is also affected by several other factors such as its length and eccentricity [4] so that varying degrees of stenosis can cause myocardial ischemia in different individuals and under different physiologic circumstances. Stenoses of intermediate severity by angiographic criteria have been shown to have widely disparate

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functional significance as assessed by fractional flow reserve (FFR) or quantitative analysis of blood flow using PET [3]. Therefore, in the clinical setting, functional studies may be necessary to ascertain the potential for myocardial ischemia. Ischemia may also occur due to endothelial dysfunction without significant stenosis at the epicardial level, and endothelial dysfunction may occur throughout the coronary vasculature from epicardial level right down to the microvasculature. Because blood flow is in the direction of subepicardium to subendocardium and oxygen requirements are greater in the subendocardial layers, the subendocardium is more vulnerable to ischemia, creating a transmural gradient of ischemia. In acute coronary syndromes, the imbalance is caused by acute reduction of oxygen supply secondary to a sudden marked reduction or cessation of coronary flow as a result of platelet aggregates or thrombi, or to increased coronary vascular tone (coronary vasospasm). Such ischemia may occur at rest as the ischemia is related to a disruption of supply rather than demand, although in many circumstances, ischemia results from both an increase in oxygen demand and a reduction in supply. Infarction follows when blood supply is interrupted completely for a critical period of time such that the ischemic damage at cellular level becomes irreversible and myocardial necrosis ensues [5]. Infarcted tissue is nonviable and will not recover function following revascularization. Multiple studies using several different modalities, both in the acute and chronic phase, have demonstrated recovery of function in viable tissue in which there is no or reversible ischemic damage [6]. Although comprehensive descriptions of the cellular changes occurring during ischemia are beyond the scope of this chapter, it is useful to distinguish between acute and chronic ischemia, as this brings into focus the concepts of stunning and hibernation. Myocardial stunning can be defined as a transient reduction in contractile function caused by a period of ischemia despite the absence of infarction that persists after normal or near-normal coronary blood flow is restored. Myocardial hibernation, on the other hand, is a state of sustained reduction of Â�contractile function in underperfused but viable myocardium, which recovers completely on successful revascularization. Myocardial hibernation as a clinical entity was first proposed in the 1980s when systematic review of the results of coronary bypass surgery trials identified patients with chronic LV dysfunction who improved on revascularization [2]. Based on these findings, Rahimtoola proposed myocardial hibernation to describe a situation of “a prolonged subacute or chronic state of myocardial ischemia in which myocardial contractility and metabolism and ventricular function are reduced to match the reduced blood supply,” which is “a new state of equilibrium . . . whereby myocardial necrosis is prevented, and the myocardium is capable of returning to normal or near-normal function on

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restoration of an adequate blood supply.” This concept is now well supported by a comprehensive body of in vitro and animal models of chronic ischemia as well as clinical studies [7]. The term chronic ischemia may be used to describe events in the setting of chronic repetitive demand ischemia or chronic hypoperfusion. In reviewing the data on imaging techniques in assessment of chronic ischemia in particular, the potential pitfalls in assessing the diagnostic accuracy of any test of ischemia must be acknowledged. Most clinical studies use coronary angiography, either visual grading of stenosis or quantitative coronary angiography, as the gold standard against which the imaging test is compared. However, there are circumstances when ischemia may occur in the presence of an arbitrarily defined nonsignificant lesion depending on the cutoff used to determine significance .50% in some studies and .70% in others. Ischemia may occur even in the absence of visible epicardial stenosis, as in Syndrome X [8], or hypertrophic cardiomyopathy [9]. Finally, ischemia may not be demonstrated in spite of the presence a coronary lesion in the appropriate artery, particularly if the reduction in the cross-sectional area is intermediate rather than severe. A true indication of the accuracy of a technique to assess (reduced) coronary perfusion is more likely from studies that use microspheres or invasive physiological measurement (FFR or coronary flow ratio) as the gold standard. But such techniques are not suited to large-scale clinical studies, and while some studies may use invasive tests of the functional severity of individual lesions to correlate against the test of ischemia [10], by far the greatest number of clinical studies still use angiographic assessment of coronary stenosis as a surrogate gold standard. Therefore, although the main parameter by which imaging techniques have been assessed to date in the literature has been their ability to determine the presence of significant obstructive coronary disease, and leading from this, their ability to predict prognosis, there is a growing understanding that this approach to diagnostic accuracy is overly simplistic. In clinical practice, questions are often far more complex, requiring greater regional precision as well as accuracy in identifying the culprit vessel or even culprit lesion to plan revascularization. In the expanding population who have had prior myocardial infarction or prior revascularization, or who have ischemic heart failure, detection of coronary disease is less often a clinical question but rather localization and quantification of ischemia either in parallel or in series with assessment of viability. How clinically available techniques may be employed to ascertain the presence or absence of ischemia and more importantly their capacity to quantitatively or semiquantitatively characterize the severity and extent of ischemia and/or viability in a manner that is relevant to estimating prognosis and determining treatment options will now be discussed.

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Imaging Ischemia

jâ•… NUCLEAR CARDIOLOGY

The detection of ischemia in chronic stable coronary disease requires that a stimulus be applied to expose regional differences in coronary flow reserve (flow heterogeneity) and/or induce an imbalance between oxygen demand and supply (ischemia). Exercise is the simplest and most physiological stress, producing regional perfusion abnormalities and ischemia. Inotropic agents such as dobutamine increase the metabolic demand through increased HR (chronotropy) and contractility coupled with some vasodilator activity, thereby simulating exercise to induce ischemia. Vasodilator stress, adenosine or dipyridamole being the most commonly administered agents, causes coronary vasodilation. Coronary blood flow increases 3- to 5-fold in normal arteries, but cannot increase to the same extent in arteries with significant stenosis, producing flow heterogeneity in hemodynamically significant and ischemia in severe coronary obstruction. The temporal sequence of events following acute coronary occlusion, known as the ischemic cascade, has been well studied [11,12] and confirmed in a model of demand ischemia [13]. Ischemic cascade begins with a perfusion deficit that is followed by hypocontractility and ST segment change, before chest pain or angina occurs. It is therefore not surprising that tests designed to detect ST segment change are in general less sensitive to detect significant coronary disease at a certain level of stress, as ST change occurs late in the ischemic cascade and may not occur in shorter or milder episodes of ischemia. On the other hand, tests that are effective in detecting perfusion deficits are likely to be more sensitive in the detection of ischemia than ST changes, given that perfusion abnormalities occur as the initial event in ischemic cascade. The modest diagnostic accuracy of exercise ECG as a tool to determine the presence of ischemia due to coronary disease (sensitivity and specificity of 68% and 77%, respectively, in a meta-analysis of 147 studies [14] and 50% and 90% in a further analysis that took referral bias into account [15]) is to be expected and is offset to some extent by its inexpensiveness, accessibility, and applicability to multiple clinical scenarios. The exercise ECG also yields important prognostic information if viewed as a comprehensive assessment including the duration of exercise, time to ischemia, hemodynamic response, and other factors rather than a simple binary measure of presence or absence of ST depression [15]. Nonetheless, exercise ECG as a tool to assess ischemia is relatively crude, limited by multiple patient- and test-dependent factors. Exercise ECG cannot reliably detect ischemia in patients with LBBB, WPW, or LVH or those on digoxin. It lacks specificity in women, and many patientsare unable to exercise for noncardiac as well as cardiac reasons. Regional localization of ischemia is extremely limited, and nonspecific changes may occur postinfarction or revascularization, making it a blunt instrument at best to investigate patients with established coronary disease.

Myocardial Perfusion SPECT With the impetus to improve diagnostic accuracy of exercise testing came the development of stress imaging techniques. Exercise radionuclide ventriculography was one of the first techniques used in the assessment of ischemia, but this was superseded in the late 1970s and 1980s by myocardial perfusion imaging. There have been a succession of changes in nuclear perfusion technology over the past 20 years but the principles remain the same. An image of the heart is created from acquisition of gamma emissions from an injected radiotracer, or higher energy emissions from the result of coincidence reactions in local tissue in the case of PET. The radiotracer must be highly extracted in the organ of interest (in this case the heart) and exhibit rapid clearance from the blood pool to allow determination of regional perfusion. The injection is performed during stress and the image acquired immediately or shortly afterward, with uptake reflecting perfusion at the time of injection. A resting image is also acquired for comparison. The first class of radiopharmaceuticals to be used to image the heart were the potassium analogs, which enter the myocardium via the sodium-potassium ATPase pump, of which thallium 201 had the most favorable physical and biological characteristics for imaging in humans. The seminal studies demonstrating the value of myocardial perfusion imaging in the 1970s utilized potassium and thallium 201 planar imaging techniques [16–18]. Most myocardial perfusion imaging today is performed using gated (which allows evaluation of ventricular function as well as perfusion) SPECT and computer-assisted semiquantitative analysis. In addition to the technical advances in scintigraphic data acquisition and analysis, the other major factor in the evolution of nuclear perfusion imaging has been the development of technetium 99m–labelled tracers. Technetium 99m tracers sestamibi and tetrofosmin have distinct advantages over thallium 201 for straightforward perfusion imaging protocol, having a higher and narrower energy peak, and shorter half-life, which allow administration of higher doses. The greater counts available contribute to higher sensitivity when compared to thallium 201 [19]. However, the use of thallium 201 continues and has certain advantages in terms of greater linearity with flow at the higher coronary flow rates observed with vasodilator stress, as well as greater sensitivity for the detection of viable myocardium [20] due to its ability to redistribute to all cells with intact cell membranes, exploited particularly in rest redistribution protocols. Dual-isotope studies are also possible with rest and stress acquisitions performed with thallium- and technetium-based tracers, respectively, to speed patient throughput. Further recent technical advances include the development of iterative reconstruction algorithms to replace filtered backprojection in image

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reconstruction, as well as cardiac-specific high-speed or Dynamic SPECT cameras and computed tomography (CT) attenuation correction, which improve sensitivity and specificity, respectively. Using modern imaging techniques and radiopharmaceuticals, the sensitivity and specificity of myocardial SPECT myocardial perfusion are 91% and 72%, respectively [21]. There is a wealth of data supporting SPECT perfusion as an effective tool in risk assessment in known or suspected coronary disease, prior to noncardiac surgery and in the acute emergency department setting, with a negative test associated with a low event rate (,1% per annum) in most studies, and the extent and severity of perfusion abnormalities showing a graded relationship with adverse events. But beyond the improvements in separation of those with and without obstructive coronary disease over exercise ECG, SPECT is capable of: (i) localization of regional ischemia allowing for appropriate planning of revascularization and (ii) quantification of the extent and severity of abnormality on SPECT allowing a more refined approach to risk assessment. Key limitations of SPECT perfusion imaging are poor spatial resolution, 15 mm for most clinical scanners, and susceptibility to attenuation artifact particularly affecting the anterior wall in large-breasted women and the inferior wall in men. Although the addition of ECG gating to the images has improved diagnostic accuracy and prognostic capability, the poor temporal resolution of the gated images allows only relatively crude evaluation of LV function. Other disadvantages include the radiation burden and the duration of study for the patient, as several hours must be allowed to elapse between stress and resting studies. PET Perfusion PET perfusion imaging developed primarily as a research tool in the 1980s, enhancing knowledge of physiological and pathological states through absolute quantification of myocardial blood flow, and has definite advantages over conventional SPECT perfusion imaging. The intrinsic differences between PET and SPECT in terms of photon energy (511 keV rather than 80–140 keV for SPECT tracers), data acquisition (coincidence detection leading naturally to tomographic image formation), and inbuilt attenuation correction result in better temporal and spatial resolution, and fewer attenuation and scatter artifacts with PET, although it must be noted that while the intrinsic isotropic resolution is of the order of 4.5 mm, the effective isotropic resolution after filtering is closer to 10 mm. A further advantage of PET is the multiplicity of tracers suitable for imaging. Nitrogen 13-ammonia and rubidium are the most commonly used tracers in clinical perfusion imaging, and oxygen 15 water is well established as a perfusion agent in the research setting. In addition to perfusion imaging, the availability of positron-emitting isotopes

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of elements important in physiological processes including oxygen 15, nitrogen 13, carbon 11, and fluorine-18 opens multiple opportunities to image metabolic and other molecular events by insertion of the isotope into natural fuel substrates, amino acids, hormones, or receptor ligands without affecting their biological function. As will be discussed later, this form of metabolic imaging is used in PET assessment of viability. Using coronary angiography as the gold standard, PET perfusion imaging demonstrates greater specificity than SPECT, .90%, but somewhat lower sensitivity (80%). A case example of inducible myocardial ischemia from multivessel coronary artery disease assessed by PET imaging is illustrated in Figure 10.1. PET perfusion testing shows excellent prognostic value with a mortality rate of 0.4% per annum in patients with a negative test [22]. Absolute quantification of myocardial blood flow is possible with PET, but the process is laborious and time consuming. A further limitation to widespread use of PET perfusion as a first-line investigation is the need to have a cyclotron on site or within a suitable distance for delivery to be completed before the tracer has decayed significantly. Rubidium may be produced from a generator without the need of a cyclotron, but the gain in diagnostic efficiency is marginal relative to the cost. Thus, although the number of centers with clinical availability of PET myocardial perfusion is growing, it is not readily available in majority of the centers and is unlikely to become so.

jâ•… STR ESS ECG ECG boasts of many advantages as an imaging technique, being widely available, portable, and unassociated with a radiation burden. Conversely, image quality and diagnostic ability may be significantly hampered by patient- and Â�operator-dependent factors. Although limited echo windows may preclude a diagnostic study in only a small proportion of cases, and fewer in the era of contrast enhancement, the skill of the operator in acquiring the images, particularly during stress, and the experience necessary to correctly interpret the images is sometimes underestimated. This may lead to the erroneous assumption that the portability of the hardware for imaging translates directly to robust widespread clinical applicability. By far, the largest body of experience in the use of ECG to image ischemia has been in the assessment of regional wall motion abnormalities in response to stress, exercise, dobutamine, or vasodilator stress (dipyridamole echo), and there is an extensive literature supporting the diagnostic accuracy of stress echo using each of these stress modalities in the detection of coronary disease [23–32]. Pharmacological stress echo using high-dose dipyridamole and dobutamine have been shown to be of similar accuracy, with sensitivity of 85% (CI 80–89) and specificity

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1 0 . 1 â•… Stress rubidium 82 perfusion images demonstrate (a) a large defect of severe intensity in the mid anterior wall, mid septum, the apical 4 myocardial segments, and left ventricular apex that was reversible at rest and (b) a medium-sized and severe perfusion defect in the entire inferior wall that was completely reversible at rest. These findings are consistent with significant dipyridamole-induced perfusion defects in 2 coronary territories, the mid LAD, and posterior descending coronary arteries. Findings of transient cavity dilation suggest significant ischemic burden and/ or underlying severe multivessel coronary artery disease. Courtesy of Sharmila Dorbala. F igure

89% (CI 82–94) in meta-analysis [33]. As regional wall motion abnormalities occur relatively late in the ischemic cascade, comparative studies with nuclear perfusion techniques tend to report overall similar diagnostic accuracies but slightly higher sensitivity for perfusion and higher specificity for stress echo techniques [34,35]. An important advantage of ECG over nuclear perfusion imaging is the capacity to investigate the physiological effects of demand ischemia rather than myocardial blood flow heterogeneity, hence its reported higher specificity than nuclear perfusion techniques for significant coronary stenosis. Stress echo also has the advantage of observing the effects on valvular function during resting and stress states. In addition to the diagnostic utility of stress ECG, the prognostic value of stress ECG is well established. A negative stress echocardiogram is associated with a low (,1% per annum) risk of major cardiac events over the next 1 to 3 years, and there is a graded relationship between the extent of regional wall motion abnormality and subsequent cardiac events [36]. As with other imaging techniques, there have been multiple advances in the availability and application of technology in the field of stress echo. Improvements in display and image quality with the introduction of second harmonic imaging have been followed by the development of techniques such as tissue Doppler imaging to

assess regional strain [27,37,38] offering real potential to improve the diagnostic and prognostic capabilities [39] of the test. Real-time 3D contrast-enhanced stress echo is Â�feasible, but as yet there is no convincing evidence that this adds sufficient incremental value to replace existing techniques, and indeed results are not entirely concordant with those of 2D stress echo [40,41]. There has also been considerable development in the field of myocardial contrast perfusion echo [42,43], and in noninvasive Doppler assessment of coronary flow reserve [44,45], but again the feasibility and incremental value of adding these techniques to mainstream application need further elucidation.

jâ•…C ARDIOVASCULAR MAGNETIC RESONANCE CMR Detection of Regional Wall Motion Abnormalities CMR offers several theoretical and practical advantages over both stress echo and nuclear perfusion. It provides substantially better temporal (#45 milliseconds as standard for assessment of ventricular function) and Â�spatial resolution (1.5 mm 3 1.5 mm in-plane resolution) to

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nuclear imaging, without the limitations associated with poor echo windows. Thus, it is an ideal tool for the investigation of wall motion and/or wall thickening in response to stress. An early work [46] demonstrated the feasibility of dobutamine stress CMR, and encouraging results for diagnostic accuracy have been confirmed. In the 15 years that have followed, at least 14 further studies have been published that used regional wall motion abnormalities on stress CMR to detect angiographically significant coronary disease, reporting sensitivities of 78% to 91% and specificities of 75% to 100%. A recent meta-analysis reports summary estimates of sensitivity and specificity of 85% and 86%, respectively [47]. During this time there have been significant improvements in cine CMR imaging that have made an important contribution to the robustness of the technique, with fast-gradient echo sequences largely superseded by cine steady-state free precession at the most common 1.5-T environment, allowing for superior myocardial to blood pool contrast. Further advances in stress CMR include a more quantitative approach to the analysis of wall motion through the use of tissue tagging. Tagging involves the placement of selective saturation bands at regular intervals through the slice of interest at the onset of image acquisition. Myocardial motion in circumferential, longitudinal, and radial dimensions throughout the cardiac cycle can then be tracked, and quantified, by analyzing the deformation of the saturation bands. Tagging correlates well with tissue Doppler measures of longitudinal and radial strain [48], and analysis of tagging improves the sensitivity of dobutamine CMR [49]. Analysis of tagged images is time consuming, but commercially available software have been developed, which allow semiautomated analysis of tagging, and have made significant improvements on the postprocessing time. In relation to the stress applied, exercise has been employed as a stressor [50], but the logistics of achieving a sufficient level of exercise to provoke ischemia are difficult within the confines of the magnet, and pharmacological stress is almost universally employed in clinical practice. As flow heterogeneity does not lead directly to ischemic wall motion abnormalities except in cases of more severe perfusion abnormality, where real ischemia is generated, it is not surprising that cine imaging during vasodilator stress tends to be associated with lower sensitivity [51] and higher specificity for the detection of coronary disease compared to inotropic drugs. In a study in which adenosine and dobutamine were compared directly, sensitivities and specificities for detection of coronary disease by cine CMR imaging were 40% and 96%, and 89% and 80% for adenosine and dobutamine, respectively [52]. The impact of detecting only severe stenoses with vasodilator stress when wall motion rather than perfusion is observed may partly explain the importance of dipyridamole-induced

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wall motion abnormalities in predicting prognosis. The presence (and extent) of wall motion abnormality with dipyridamole stress has been shown to be the CMR variable most predictive of subsequent clinical events during follow-up of 420 days in a large study of the prognostic impact of stress MR [53]. Recently, 2 studies have highlighted the clinical utility of dobutamine cine CMR in cardiac stress testing. Nagel et al [54] compared ischemiainduced wall motion abnormalities between dobutamine cine CMR and dobutamine stress ECG with harmonic imaging in 208 consecutive patients with suspected CAD prior to cardiac catheterization. Dobutamine cine CMR provided better sensitivity (89% vs. 74%) and specificity (86% vs. 70%) than dobutamine stress ECG for detecting .50% coronary artery stenosis. Similarly, Hundley et al performed dobutamine cine CMR on 163 patients with poor echocardiographic windows and demonstrated Â�sensitivity and specificity of both 83% in detection of .50% coronary stenosis on quantitative coronary angiography [55]. In addition, dobutamine cine CMR was associated with a negative predictive value of 97% for cardiac events over the subsequent 8-month period [56]. Stress CMR can therefore be used as both a diagnostic tool and an aid to prognostic evaluation of patients with known or suspected coronary disease. In addition, as with stress echo, Dobutamine CMR is useful not only for the detection, localization, and quantification of ischemia but also to identify the effects of ischemia on valvular function. An illustrative case demonstrating biphase regional response in LV function is demonstrated in Figure 10.2.

jâ•… MR MYOCARDIAL PERFUSION MR myocardial perfusion, having evolved considerably in the past decade, is now a clinically useful tool rather than a research investigation, with significant advantages for the assessment of chronic ischemia and viability. In particular, the comprehensive nature of assessment whereby function, perfusion, and viability can be optimally assessed in a Â�single sitting is attractive for patients and health care providers alike. The following sections outline the principles of MR myocardial perfusion imaging, the sequences and contrast agents employed in the clinical arena, the analysis of the results, the clinical utility of the test, and the challenges posed by the technique. In addition, wider developments in the field of MR perfusion and imaging of ischemia will be discussed. The contrast between the blood and myocardium with MR depends largely on the proton concentration and longitudinal (T1) and transverse (T2) relaxation times. This inherent contrast may be modulated through the use of MR contrast agents or different pulse sequences weighted to emphasize T1 or T2 effects. For myocardial perfusion

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F igure 1 0 . 2 â•… Dobutamine stress cardiovascular magnetic resonance of a 54-year-old patient who complained of chest pain suspicious of CAD. Cine stress wall motion imaging (apical short axis and 3-chamber views) demonstrated an inducible wall motion abnormality (black arrows) in the anterior wall at peak-dosed stage (40 μg/kg/min). Panels A–D represent the diastole and systole of short-axis cine SSFP on rest and during peak-dosed stage. Panels E–H represent the diastole and systole of a 3-chamber cine SSFP on rest and during peak-dosed stage.

imaging, efforts have been concentrated on expanding the contrast between areas of normal and relative hypoperfusion through the introduction of contrast agents, which increase or decrease signal intensity (SI) in accordance with an established relationship with coronary blood flow. First-Pass Gadolinium Perfusion Imaging While research is ongoing into refining and developing alternative methodologies to assess myocardial perfusion, the technique that has achieved greatest clinical prominence is first-pass perfusion imaging using gadoliniumbased extracellular contrast agents in combination with T1-sensitive pulse sequences. A major factor in the success of this technique has been the advent of extremely

Multimodality Imaging in Cardiovascular Medicine

fast sequences capable of acquiring sequential images of each of several myocardial slices, each capturing the relative differences in SI throughout the myocardium, at multiple closely spaced time points. While T1 weighting may be introduced by saturation, a notched saturation prepulse, or inversion recovery, a saturation prepulse is most commonly applied to null the myocardium. For readout, fast imaging techniques such as fast spoiled gradient echo, echo planar imaging, and balanced steady-state free precession have been used in combination with parallel imaging techniques [57] to Â�further increase the speed of acquisition with least compromise to spatial resolution. The relative lack of standardization of sequences for perfusion across vendors and centers has, until relatively recently, been a limitation to the comprehensive study of the clinical utility of MR perfusion. Gadolinium is a naturally occurring metal element with paramagnetic properties due to an unpaired electron on its outer electron orbit. Gadolinium is highly toxic in its pure state; hence, gadolinium-based contrast agents used routinely for clinical purposes are chelates. Each consists of a gadolinium molecule chelated to a linear or cyclic multidentate ligand to create a biologically inert and thermodynamically stable complex. These agents shorten both T1 and T2, but the predominant effect at low dose is T1 shortening; thus, areas of contrast uptake are seen as hyperintense (bright) on T1-weighted images. There are several commercially available extracellular contrast agents, all with similar T1 and T2 relaxation properties, with the exception of Gd-BOPTA (MultiHance), which has approximately twice the T1 relaxivity in blood (9.7 mmol/s) of standard gadolinium contrast media. Gd-BOPTA (MultiHance), Gd-DPTA (Magnevist), Gd-DOTA (Dotarem), Gd-DTPADMA (Omniscan), Gd-DTPA-BMEA (Optimark), and Gd-HPDO3A (ProHance) are all extracellular contrast agents available in 0.5 mol concentration. Gd-DO3A butriol (Gadovist) is also available at 1.0 mol concentration. For myocardial perfusion imaging, dynamic imaging is conducted as the contrast agent is injected through the circulation in a compact bolus. Up to 60 phases are acquired for each slice to capture the myocardium and blood pool precontrast, the contrast then fills the right ventricle and the left ventricle before perfusing the myocardium, resulting in enhancement of the myocardial walls. On the first pass through the capillary bed, up to 50% of circulating Gd-DTPA diffuses from the intravascular compartment to the extravascular compartment [58]. Therefore, although recirculation is imaged, for both visual and quantitative analysis, the most important portion of the acquisition is during the initial first pass when the contrast enters and washes out of the myocardium for the first time. Differences in SI between areas of myocardium reflecting areas of perfusion heterogeneity can be detected visually or analyzed semiquantitatively or quantitatively using the resultant time-intensity curves.

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Requirements and assumptions that must be met for MR myocardial perfusion to produce an accurate and clinically meaningful result are outlined below: 1. Image parameters • Adequate temporal resolution, that is, 1 image per heart beat • Acquisition window as short as possible to reduce blurring • Acceptable spatial resolution (approximately 2 mm inplane, to allow discrimination of transmural gradient) • Constant magnetization to ensure similar T1 weighting across slice locations • Coverage of the left ventricle maximized as far as possible • Contrast-to-noise and signal-to-noise ratios should be sufficient to discriminate between normal and hypoperfused myocardium 2. Contrast dosage and administration • Direct linear relationship between contrast dose and SI—true at low-dose contrast but not at high (.0.12 mmol/kg) dose • Compact bolus of contrast facilitated by saline chaser • Contrast injection rate of 5–7 mL/s Experimental models of first-pass perfusion employ left atrial catheter placement for contrast injection [59], but it is neither possible nor necessary to reproduce such conditions for clinical scans. Peripheral intravenous cannulation, preferably in the antecubital fossa is sufficient for delivery of contrast. More important is the rate of contrast delivery, .3 mL/s, preferably .5 mL/s, and the coadministration of a saline bolus immediately after the contrast to ensure a compact bolus to facilitate both visual and quantitative analysis. Perfusion imaging to quantify ischemia is generally performed at rest and during stress for comparative purposes and to allow calculation of the myocardial perfusion reserve, although stress-only protocols have been validated [60]. Vasodilator stress using adenosine or dipyridamole is most commonly used, due to the excellent safety profile and tolerability of these agents [61], but dobutamine may be used as an alternative. However, dobutamine perfusion imaging with MR is complicated by the increase in HR, which may limit adequate coverage of the left ventricle during stress perfusion, as the number of slices that can be prescribed is inversely related to the patient HR. For patients undergoing vasodilator stress, depending on the sequence used, 3 to 6 short-axis slices may be combined with one or more longaxis views of the left ventricle to facilitate assessment of apical perfusion. If a notched-pulse preparatory sequence is employed, the combination of long- and short-axis planes is not possible, but this disadvantage may be somewhat offset if coverage of the left ventricle is maximized by prescribing as many short-axis slices as can be accommodated in the available time within the cardiac cycle.

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Consideration should be given from the outset to the type of analysis to be undertaken as the dose administered will affect quantification of perfusion. At low doses, the relationship between contrast dose and SI is approximately linear, but at higher doses (.0.12 mmol/ kg) this relationship no longer holds true [62]. A potential conflict between the requirements for quantitative or visual analysis as the greater contrast-to-noise available with the use of higher dose (0.1–0.15 mmol/kg) facilitates detection of perfusion defects by visual analysis, but signal saturation may render quantitative analyses less reliable at higher doses. For clinical purposes, qualitative visual analysis yields very acceptable diagnostic accuracy. In a study of a population with Non- ST Elevation Myocardial Infarction (NSTEMI), the sensitivity and specificity of visual assessment of perfusion alone (using a dose of 0.05 mmol/kg) were 88% and 83%, respectively [63]. In the same study, comprehensive assessment of MR information including late enhancement increased the sensitivity to 96%. In another study in which fewer than 50% of the population had prior myocardial infarction, the sensitivity and specificity of visual assessment of perfusion (using a dose of 0.1 mmol/L) for the detection of coronary disease were 93% and 85%, respectively [64]. However, quantitative or at least semiquantitative techniques are desirable for both clinical and research purposes. Quantification of Perfusion Most semiquantitative techniques involve regional analysis of the time-intensity curve. Using an accepted model of LV segmentation (such as the 17 segment AHA model) [65], the LV wall can be divided into regions corresponding to those used to analyze wall motion abnormality or late enhancement. A region of interest is placed within the myocardial segment (or within the different layers of the myocardium, subepicardium to subendocardium, if so desired) during sequential phases, with care to track a consistent portion of the LV wall notwithstanding the presence of ectopic beats or respiratory movement, and to avoid blood pool contamination and/or other potential causes of error. The SI within the region of interest is depicted as a function of time and from this a number of parameters may be measured, which can be related to perfusion, as listed below: 1. The rate of increase in SI or upslope after the bolus of contrast 2. The maximum SI increase 3. The time to maximum increase in SI 4. The time from contrast appearance in the LV cavity to contrast appearance in myocardium 5. Time to 50% maximal SI 6. The rate of decrease in SI after peak 7. The mean transit time using an exponential fit

Multimodality Imaging in Cardiovascular Medicine

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Of these, the upslope or rate of increase in SI is emerging as the most suited semiquantitative analysis to clinical application due to the depth of data validating its robustness and diagnostic accuracy [60,66–68]. A recent dose-ranging study using myocardial upstroke as the semiquantitative measurement parameter found that doses of 0.1 and 0.15 mmol/kg were superior to 0.05 mmol/kg for the detection of coronary disease [60], with pooled sensitivity and specificity of 93% and 75%, respectively. Using the upslope of the curve renders calculation of the myocardial perfusion reserve index (MPRI) relatively straightforward. MPRI 5

Upslope of SI curve during hyperemia Upslope of SI curve at rest

Absolute quantification of myocardial blood flow is possible, although it requires considerably more complex modeling and is subject to several important confounders. These include nonlinearity in the relationship between SI and contrast most pronounced at higher contrast dose, temporal differences between images in the saturation pulse that creates T1 weighting, uncertainty that the rapid exchange condition is met, as well as regional variation in the main magnetic field (B0) or radiofrequency field (B1). Measurements of absolute regional myocardial blood flow (in mL/g/min) can be made by mathematical deconvolution of the time-intensity curve using one of several models including the Fermi [69] or modified Kety techniques [70]. Deconvolution modeling requires a measured arterial input function, usually from the LV cavity or ascending aorta. Measurement of the true arterial input function is affected by short T1s and T2* effects that occur with high-contrast agent concentrations during bolus contrast agent passage in the blood pool. Two different strategies have been proposed to overcome this problem, the dual-bolus method [71,72] or the dualsequence method [73–75]. Clinical Utility of MR Myocardial Perfusion The preliminary reports of the clinical feasibility of the firstpass technique in patients [76] have been followed by multiple studies confirming its feasibility, documenting technical advances in terms of sequence design, and demonstrating highly satisfactory diagnostic performance indices. In 2000, Al-Saadi et al reported per-coronary sensitivity and specificity of 90% and 83% for the detection of coronary stenosis .75% in a population with suspected coronary disease (n 5 40), using an inversion recovery Â�single-shot turbo gradient echo technique with dipyridamole stress [67]. Ishida et al reported per-patient sensitivity of 90% and specificity of 85% in a similar but larger population (n 5 104) using qualitative analysis, dipyridamole stress, and fast echo planar readout with a notched interleaved saturation preparatory pulse [77]. In the same year, Nagel et al reported

sensitivity and specificity of 88% and 90%, respectively, in a cohort of 90 patients using adenosine stress [68]. Similar excellent results have been reported more recently for adenosine perfusion imaging in a larger patient cohort (n 5 176), sensitivity 96% and specificity 83% for the detection of stenosis .70% [78] using hybrid fast-gradient echo and echo planar imaging technique. In a meta-analysis that pooled data from 14 studies of perfusion tested against coronary angiography as gold standard, the summary estimates for sensitivity and specificity were 91% and 81%, respectively [47]. These studies were relatively small single-center studies, and in the metaanalysis, diagnostic accuracy was assessed only in terms of detection of angiographic stenosis. Thus, the widespread applicability of the technique in a clinical context based solely on these results would be questionable. However, there is substantially greater depth to the evidence supporting the utility of myocardial perfusion. Single-center results have been reproduced in multicenter settings [79], and MR perfusion compares well with other available methods of noninvasive assessment of perfusion. Comparative studies with existing nuclear perfusion techniques suggest that MR perfusion imaging could realistically be used as an alternative, with superior performance relative to SPECT [80] and excellent agreement with the reported PET perfusion data [66]. Comparisons with invasive physiological measurements such as FFR have also yielded favorable results. Rieber et al showed that calculation of the Â�myocardial Â�perfusion reserve index (with a cutoff of 1.5) enabled detection of hemodynamically important stenoses, as determined by FFR of .0.75 [10]. With increasing Â�emphasis in the cardiology community on physiological data to aid appropriate selection of lesions for percutaneous intervention, and evidence that calculation of FFR may improve selection [81,82], noninvasive pre-procedural assessment of perfusion by MR is likely to prove beneficial. Beyond diagnosis and prediction of the hemodynamic significance of stenoses, MR myocardial perfusion has been shown to be an important method to determine prognosis. In a population with chest pain presenting to the emergency department, MR perfusion has been shown to have a sensitivity of 100% and a specificity of 93% in predicting subsequent death due to myocardial infarction or detection of coronary stenosis over a 1-year follow-up [83]. In another study of 218 patients with negative perfusion studies followed up for 2 years, there were no deaths or infarction, 1 percutaneous intervention, and 1 coronary artery bypass operation [84]. Jahnke et al used both adenosine myocardial perfusion and dobutamine MR for wall motion abnormalities to study 493 patients who were subsequently followed up for 3 years [85]. In this study, stress MR, either perfusion or wall motion, contributed incremental value over traditional factors such as age, gender, tobacco smoking, and diabetes in risk stratification, although combination of both techniques did not further

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increase the yield in a statistically significant manner. A normal perfusion study was associated with an extremely low event rate, 0.7% at 2 years and 2.3% at 3 years and an abnormal perfusion study with corresponding rates of 6.2%, 12.2%, and 16.3%. In multivariate analysis, adjusting for other risks, detection of a perfusion abnormality was associated with a 10-fold increase in risk of hard events (death or myocardial infarction). In light of the convincing evidence supporting the diagnostic and prognostic value of stress MR in the detection if ischemia, it can no longer be considered an investigative technique but recognized as a first-line investigation in the appropriate clinical setting [86]. A case example is illustrated in Figure 10.3, and semiquantitative measurement of myocardial perfusion by SI versus time curves of this case is shown in Figure 10.4. Evidence also suggests that dobutamine stress can also achieve near-adenosine level of vasodilatation. In Figure 10.5, we show such an example of dobutamine-induced perfusion abnormality without evidence of myocardial infarction in a patient with critical coronary artery disease. Future Directions in Perfusion MR Developments in MR perfusion can be broadly categorized as occurring in the imaging sequences or contrast agents. Aims in sequence development are to further improve spatial resolution, increase ventricular coverage, and limit artifacts. The potential for increased signal-to-noise ratio and contrast enhancement to be used to improve spatial resolution and image quality has been realized with the advent of clinical 3-T systems , and preliminary reports demonstrate promise for improved clinical diagnostic accuracy [87]. Other investigators are pursuing methods of speeding image acquisition, such as k space and time-sensitive encoding with parallel imaging (kt SENSE), to improve spatial resolution to the level achievable with cine or

F igure 1 0 . 3 â•… Example of an adenosine stress cardiovascular mag-

netic resonance performed in a 57-year-old male with hypertension, obesity, and atypical chest pain revealing normal resting biventricular function associated with a first-pass perfusion defect during vasodilator stress involving the entire inferior wall and midinfero lateral walls. Panels A–D: 4-chamber and 2-chamber cine SSFP demonstrating normal resting function. Panels E and F: First-pass gadolinium perfusion during rest (E) and during vasodilator stress (F) demonstrating a clear perfusion defect involving the mid to distal inferior and mid-inferolateral walls (white arrows).

F igure 1 0 . 4 â•…The graph represents the signal-intensity curve in 3 different regions of interest (inferior wall, anterior wall, and blood poll) as a function of time immediately after bolus infusion of gadolinium during the adenosine vasodilator stress cardiovascular magnetic resonance depicted in Figure 10.3. The inferior wall (blue curve) demonstrated a remarkable lower level of signal intensity compared to the anterior wall (orange curve). The red curve represents the blood pull.

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F igure 1 0 . 5 â•…Example of an adenosine stress cardiovascular magnetic resonance ordered for a preoperative evaluation in 78-year-old female which revealed a large-sized subendocardial first-pass perfusion defect during stress involving the mid inferior wall, infero-lateral, and infero-septal walls in the absence of any evidence of myocardial Â�infarction on the late gadolinium enhancement images (E and F). Panels A and B: Mid ventricle short-axis cine SSFP showing normal left ventricular function. Panels C and D: First-pass gadolinium perfusion during rest (C) and during dobutamine stress (D) demonstrating a large-sized subendocardial perfusion defect involving the mid to distal inferior, mid-inferolateral walls, as well as the inferoseptal wall (arrows).

late-enhancement imaging (,1.5 mm 3 1.5 mm in-plane) [88]. Clinical benefits would include the potential to image right ventricle perfusion and to facilitate greater integration of cine, perfusion, and late-enhancement images. Although, as discussed above, extracellular gadoliniumbased agents are the mainstay of myocardial perfusion imaging in the clinical setting, assessment of myocardial perfusion may be performed with endogenous as well as exogenous contrast agents. Exogenous contrast agents may be further classified according to cellular distribution (intravascular, intracellular, or extracellular), the effect on SI (increase in SI with paramagnetic agents or decrease in SI with supermagnetic agents), or specificity for target tissue (eg, for ischemia or necrotic tissue) [89]. One example of endogenous contrast in CMR is blood oxygen level dependency (BOLD) imaging, which operates on the principle that deoxygenated hemoglobin is paramagnetic and causes signal loss in T2*- or T2-weighted images. BOLD has been used to assess changes in myocardial venous

Multimodality Imaging in Cardiovascular Medicine

blood oxygenation secondary to perfusion changes in human as well as animal studies, and has demonstrated characteristics that capture the abundance of deoxygenated hemoglobin downstream from a severe stenotic coronary lesion. While BOLD is currently not yet at the stage of clinical application, it has the advantage of characterizing a unique physiologic consequence of coronary artery disease without any need for endogenous contrast. Arterial spin-labeling is another experimental method that uses endogenous contrast to assess myocardial perfusion. Both BOLD and arterial spin-labeling may be advantageous in a 3-T environment, given a higher signal to noise level compared to 1.5 T. Intravascular or blood pool contrast agents are closer to clinical application and offer potential advantages over existing contrast agents in regard to the possibility of equilibrium perfusion imaging, as well as or instead of first-pass perfusion. Of the intravascular agents, vasovist is currently licensed for clinical use in the 27 member states of the European Union. Blood pool contrast agents can also be used to determine viability in a fashion similar to extracellular contrast agents [90,91], but require a longer period between administration and imaging, 30 minutes vs. 10 minutes for extracellular contrast agents. Whether advantages in perfusion will be sufficient to outweigh the disadvantage of prolongation of the scan time to obtain viability information is a question that remains to be answered.

jâ•… VIA BILITY AND HIBERNATION The importance of accurate description of myocardial viability cannot be overestimated. Postinfarction assessment of the extent of viability allows prediction of recovery of LV function, and in the chronic ischemic setting, quantification of viability is an important aid to management decisions regarding revascularization. With improved case fatality indices for most acute presentations of coronary disease, and an aging population, heart failure has become the modern day epidemic in cardiology [92]. Heart failure is a leading cause of morbidity and mortality in developed countries, with ischemic cardiomyopathy being the most common etiology [93]. Several methods have been developed to ascertain if dysfunctional myocardium has the potential to recover function, whether in response to surgical or percutaneous revascularization, or after pharmacological reperfusion therapy. Techniques may demonstrate viability through identifying contractile reserve, cell membrane, and mitochondrial integrity, or preserved metabolic function (glucose utilization or high-energy phosphates). Nuclear cardiology techniques and stress ECG have been widely used clinically for a considerable period of time, and it is from these modalities that the greatest amount of observational data supporting the role of viability testing are available, but the literature is limited in several regards. Many studies use regional ventricular function as the outcome of

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interest, which is of undefined clinical benefit in the longer term, and studies that have evaluated clinical events are nonrandomized observational studies with the inherent bias implicit in this design. However, notwithstanding these limitations, the important trends evident from these studies include the following: (i) Medically treated patients with evidence of viability have the lowest survival, and revascularization to these patients can lead to better survival, free of infarction [6]. (ii) Improvements in heart failure symptoms and exercise capacity after revascularization are at least moderately related to the extent of viable myocardium demonstrated by pre-revascularization [94]. Nuclear Cardiology Viability may be determined by gamma radiation or PET FDG (18Fluorodeoxyglucose) techniques. The latter relies predominantly on demonstration of preserved glucose utilization in FDG PET imaging, and the former on cellular or mitochondrial integrity. Thallium 201 was the first radiotracer used to assess viability, with planar imaging now replaced by SPECT as alluded to before. As a potassium analog, regional uptake depends on regional flow and an intact sarcolemma. Uptake is reduced in infarcted or necrotic myocardium. A stress redistribution protocol may underestimate the extent of viability, and stress reinjection protocols are generally used if viability is the clinical question [20,95]. Viability is determined by the uptake of thallium in the region of interest as percentage of maximum

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uptake, with 50% to 60% being the cutoff used [96]. Because of their shorter half-life, higher energy technetiumbased radiotracers are now used more frequently than thallium, in combination with gated acquisition and more recently CT attenuation. Initial studies estimated that technetium-based sestamibi underestimated viability by 36% [97] versus PET and thallium SPECT. Improvements in protocols and quantitation have diminished the discrepancies between the techniques [98], although sensitivity is still less than with PET techniques. A recent study using CT attenuation correction reported an increase in sensitivity of adenosine stress sestamibi to detect viability determined by PET from 83% to 100% without a significant change in specificity, but this has not been reproduced in a large patient cohort [99]. Pooled results of 20 studies with 488 patients using sestamibi revealed a sensitivity of 81% and specificity of 66% to predict recovery of function after revascularization in one meta-analysis [100]. For many years, PET was considered the gold standard for the determination of viability [101]. Preserved metabolic activity as measured by FDG is indicative of viable myocardium. The combination of metabolic imaging with perfusion data, as from nitrogen 13 ammonia or oxygen 15, allows identification of matched and mismatched defects. Simplistically, areas of hypoperfusion where there is no or reduced FDG uptake, a matched defect, denote nonviable myocardium. An area of hypoperfusion associated with normal or increased FDG uptake, flow metabolism mismatch, denotes viable myocardium. Figures 10.6 and 10.7

F igure 1 0 . 6 â•…Rest rubidium 82 perfusion and 18Fluorodeoxyglucose images demonstrate a large-sized defect of severe intensity in the entire inferior and inferolateral walls with a matched reduction in glucose utilization. These findings are consistent with transmural myocardial scar in the distribution of the left circumflex coronary artery. These findings suggest that the likelihood of improvement in left ventricular systolic function following successful revascularization is low. Courtesy of Sharmila Dorbala.

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Multimodality Imaging in Cardiovascular Medicine

F igure 1 0 . 7 â•…Rest rubidium 82 perfusion and

18 Fluorodeoxyglucose images demonstrate a large-sized defect of severe intensity in the entire anterolateral wall, the mid anterior and anteroseptal walls, the apical 4 myocardial segments, and LV apex with a significant mismatch in glucose utilization (reduced perfusion but preserved glucose utilization). These findings are consistent with a large region of significant hibernating myocardium in the distributions of the mid left anterior descending coronary artery and the first diagonal or obtuse marginal coronary artery. These findings suggest that the likelihood of improvement in left ventricular systolic function following successful revascularization is high. Courtesy of Sharmila Dorbala.

demonstrate 2 case examples of PET viability assessment using rubidium 82 perfusion matching with FDG imaging. Numerous studies have been performed that have validated this principle, and assessed the ability of PET to determine viability, with generally higher reported sensitivities, 93% in meta-analysis, with a specificity of 58% [100] than for thallium of technetium SPECT studies. However, PET has a number of limitations, including radiation burden, limited spatial resolution, cost, and the complexity in acquisition and analysis of the data. Stress ECG Dobutamine stress ECG has also been extensively employed to assess myocardial viability. Stress ECG relies on demonstrating contractile reserve with dobutamine administration. The protocol is somewhat different to a standard dobutamine

stress echo, as the greatest interest is in the events during the low-dose range. In viable hibernating myocardium, a region which is hypokinetic or even akinetic at rest demonstrates improved contractility at low-dose dobutamine. This may be followed by deterioration as the metabolic demands come to exceed the coronary flow that is available across a tight and fixed coronary stenosis, the so-called biphasic response. Demonstration of contractile reserve predicts functional recovery [102]. Stress echo is estimated to detect viable Â�myocardium with a somewhat lower sensitivity and higher specificity than nuclear techniques, 81% and 80%, respectively, in a meta-analysis including 32 studies, and more than 1000 patients. Agreement between nuclear cardiology and stress echo is rather poor, as low as 68% in one study [103]. Agreement is substantially higher in segments without contractile reserve, with discrepancies arising in regions

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that demonstrate tracer uptake but not contractile reserve, underlining the intrinsically higher specificity of stress echo. In one direct comparison study using PET, thallium and technetium SPECT, and stress echo, the nuclear techniques had high negative predictive values of greater than or equal to 95% but lower positive predictive values, 45% to 75% as compared with ECG, which had a negative predictive value of 87% and a positive predictive value of 100%. In this study, PET was the most powerful predictor of hibernation, although the combination of a technique with a high positive predictive value (ECG) and a high negative predictive value (PET or sestamibi) was suggested by the authors as a pragmatic clinical course where there was doubt [104]. Both harmonic imaging and intravenous blood pool echo contrast may be used to improve endocardial definition, and newer more quantitative techniques hold promise for improvements in the sensitivity of stress echo to detect hibernating myocardium in the future [105]. However, although widely available and less technically complex, ECG is limited by its qualitative assessment, with high interobserver and intercenter variation, and inadequate acoustic windows in a substantial number of patients, even with harmonic imaging and contrast. CMR Assessment of Viability CMR can provide cine contractile reserve, perfusion, and high-resolution quantitation of infarct transmural extent, and can thus potentially overcome the limitations of both dobutamine echo and nuclear techniques. Demonstration of contractile reserve, similar to stress echo, was the first approach to CMR assessment of viability, but the technique has evolved considerably particularly during the last decade with the clinical introduction of late gadolinium enhancement (LGE) imaging [106]. Viability can now be assessed by a variety of methods, with LGE techniques emerging as the new clinical gold standard [107]. CMR methods to assess viability: 1. Wall thickness at rest/during stress, and contractile reserve 2. LGE (washin/washout) using extracellular agents 3. Necrosis-specific contrast agents 4. Energetic differences expressed as differences in ATPto-PhosCr ratio

Wall Thickness and Contractile Reserve In line with echocardiographic data [108], severely thinned myocardium is unlikely to recover function. Baer et al have shown that a diastolic wall thickness of 5.5 mm could be used to discriminate regions of myocardium with preserved metabolic function and those without, as assessed by FDG PET [109]. In a subsequent article, the group demonstrated that recovery of function never occurred if diastolic wall thickness was ,5.5 mm [110]; however, the converse was

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not always true, that is, recovery did not universally occur in regions with wall thickness .5.5 mm. Thus, assessment of the diastolic wall thickness, while sensitive, is poorly specific in the detection of recovery of function. In the study by Baer et al the addition of the observation that a contractile reserve of regional wall thickening of 2 mm during low-dose dobutamine greatly improves the specificity of the technique increased the test specificity to 92% with a maintained sensitivity of 86%, to predict functional recovery after revascularization [110]. Similarly, high sensitivity and specificity have been reported in some [111] but not all studies [112]. A consistent finding in studies of dobutamine stress CMR, however, is the high specificity of the technique, similar to stress ECG [113]. On a less subjective level, tissue tagging and analysis of strain offer the potential of a more quantitative approach, although whether this will translate to greater clinical benefits is yet to be proven [105].

Late Gadolinium Enhancement Superb tissue characterization is one of the major advantages of CMR, and exploitation of this potential through the use of contrast-enhanced T1-weighted imaging to define the infarcted and irreversibly damaged portion of myocardium has been one of the most significant step forward in CMR in the past decade [106]. While the exact reasons for hyperenhancement in areas of replacement (or interstitial) fibrosis remain a topic of intense scrutiny, the likely mechanism is a combination of delayed washin and washout kinetics of nonviable tissue and different volumes of distribution of Gd in viable and nonviable regions. Injected extracellular gadolinium contrast agent is retained in the necrotic tissue of myocardial infarction, while in normal myocardium, gadolinium is excluded from the myocyte intracellular space. In the acute setting, sarcolemmal membrane integrity is lost in cell death, allowing gadolinium to extravasate into the myocyte and resulting in hyperenhancement. In the chronic setting, scar tissue has increased extracellular collagen and a larger interstitial space than normal myocardium. This larger interstitial space accounts for LGE seen in scar [106]. While some animal studies have shown that the size and transmural depth of infarction may be slightly overestimated (9%–12%) in the immediate postinfarction period, these are stable indicators of scar extent beyond 1 week. Sequence Design and Improvements A T1-sensitive inversion recovery sequence is employed to maximize the contrast between normal and enhanced myocardium, using either FLASH or SSFP readout [114,115]. The inversion recovery prepulse allows for differentiation of normal or infarcted myocardium but is dependent on correct setting of the TI (inversion time) to null (blacken)

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normal myocardium and interactive modification of this setting as necessary during the acquisition of sequential slices to achieve optimal contrast between the normal and infarcted myocardium. Using this technique, infarcted areas appear bright, can be localized according to standardized descriptors of LV anatomy [65], and can be quantified both in terms of the circumferential and longitudinal extent of myocardium affected as well as transmurality, the transmural extent of infarction being the crucially important factor in determining the potential for recovery of infarcted myocardium. Standard 2D inversion recovery LGE imaging has been shown to be a highly reproducible technique. In addition, major advances have been made toward reducing the influence of correct selection of T1 time through the use of the phase-sensitive inversion recovery technique, which minimizes the effect of small T1 differences on contrast [116], and the use of 3D IR techniques, with or without respiratory navigator, show considerable promise as clinically useful tools to reduce image acquisition time [117]. Other avenues of active research include the development of black-blood techniques to assess myocardial viability, with the aim of improving contrast definition between blood pool contrast and subendocardial infarction, and the integration of functional and tissue contrast information into a single acquisition, with the potential to further reduce scan times and reduce misregistration [118,119].

Multimodality Imaging in Cardiovascular Medicine

segments with .75% transmural extent of infarction demonstrated recovery of function, with similar patterns observed for all dysfunctional segments. Subsequent studies by other groups have corroborated these results [111,125,126]. Beyond the response to revascularization, the extent of viable myocardium in ischemic cardiomyopathy has also been shown to be predictive of response to beta blockade [127], and CMR assessment of myocardial scar may prove useful in selection of patients who will benefit for resynchronization therapy [128]. Figures 10.8 through 10.10 illustrate common clinical scenarios where LGE imaging by CMR determines myocardial viability and aids in patient management. Comparison With Other Techniques to Detect Viability In terms of detection of scar and differentiation from viable myocardium, the superior spatial resolution with magnetic resonance compared to nuclear techniques offers

Clinical Utility of LGE Experimental and clinical studies indicate that the extent of LGE is reproducible and closely correlates with the size of myocardial necrosis or infarct scar as determined by established in vitro and in vivo methods [120–122]. The excellent spatial resolution afforded by CMR allows nearidentical registration of scar when matched with histopathological slices. Subendocardial LGE is sensitive and highly specific for the detection of myocardial infarction [120]. In addition, the detection of myocardial LGE is associated with a significantly increased risk of subsequent death and adverse cardiac events, adding incremental prognostic information to assessment of LV function [123,124]. Finally, the extent of LGE is emerging as a potent tool to determine response to novel medical and interventional therapies. The seminal study in this field from Kim et al assessed the effect of revascularization on regional recovery of function according to transmural extent of infarction by CMR in patients with ischemic LV dysfunction. The likelihood of functional recovery (per segment) was inversely related to the transmural extent of infarction. Of akinetic and dyskinetic segments with 0 to 25% transmural extent of infarction, 82% showed recovery of function; of similar segments with 26% to 50% transmural extent, 45% showed recovery of function; of segments with 51% to 75% transmural extent, 7% recovered; and none of the

F igure 1 0 . 8 â•…A 54-year-old male with a history of prior inferior myo-

cardial infarction referred for viability assessment. The cine SSFP images (A–D) showed a mildly reduced LV systolic function (LVEF 5 54%) associated with akinesis of the basal and mid inferior and infero-septum. The late gadolinium enhancement images (E and F) provided a detailed characterization of inferior myocardial infarction revealing a near-transmural late gadolinium enhancement involving basal to mid inferior and inferoseptal walls of LV as well as the inferior aspect of the RV associated with microvascular obstruction in the subendocardial region of the inferior wall infarct.

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considerable advantage. In a porcine model of chronic infarction, LGE imaging was compared to SPECT, PET, and TTC staining on histology. In this study, CMR LGE imaging showed the closest correlation with TTC measured necrosis. PET slightly overestimated the regions of necrosis and was unable to distinguish transmural and nontransmural infarcts as CMR was [129]. This is a common finding in head to head comparisons between PET, SPECT, and

F igure 1 0 . 9 â•…An example of nontransmural myocardial infarction.

The late gadolinium enhancement (LGE) images (A–D) show a subendocaridal myocardial infarction involving the mid to distal lateral wall. Note that the LGE involves less than 50% of the myocardial wall thickness (black arrows). The white line in the upper panels (A and B) represent the localization of each short-axis LGE.

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CMR LGE techniques [66,130–132], and contributes to greater sensitivity in the detection of infarction, important for prognostic reasons, but also contributes greater sensitivity in the detection of viable tissue surrounding infarction, which may recover with revascularization. Beyond the intrinsic differences in spatial resolution, due to significantly greater temporal resolution, CMR assessment of ischemia and viability allows for a simultaneous assessment of ventricular volumes, contractile reserve, and valvular function, which is not possible with nuclear techniques. CMR assessment of volumes may be useful in identifying severely dilated ventricles (ESV .153 mL), where revascularization is less likely to produce the expected improvement in function [133,134]. Additional mitral valve repair can be guided by CMR [135], and thus, this technique has been advocated as the optimal technique to plan ventricular restoration surgery [136]. With CMR, the assessment of a particular individual may be tailored specifically to one or more clinical questions, to assess perfusion, viability or contractile reserve, or all of the above, and the answer(s) obtained in a single test, of no longer than 1 hour duration, rather than serial or parallel tests over several days or even weeks. The absence of ionizing radiation is reassuring in the context of patients who may need serial reevaluation over a period of years. Currently, CMR is limited by the presence of metallic biomedical devices such as automated internal cardiac defibrillators and pacemakers, claustrophobia in a minority of patients (10%), and gadolinium contrast use in patients with end-stage renal disease leading to the rare condition of nephrogenic systemic fibrosis.

F igure 1 0 . 1 0 â•…A 63-year-old man presented to ER with inferior ST elevation myocardial infarction after 15 hours of the onset symptoms. The patient

underwent a proximal percutaneous coronary intervention (PCI) of the right coronary artery (RCA), and the cardiovascular magnetic resonance was ordered to assess left ventricle function and to evaluate the extent of the myocardial infarction. Upper panels (A–C) represent the 2-chamber late gadolinium enhancement (LGE) showing a full-thickness inferior myocardial infarction. The lower panels (D–F) represent the apical, mid, and basal short axis LGE. The white lines in upper panels denote the location of each lower short axis LGE and are very useful to evaluate the myocardial infarction extent.

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jâ•… CONCLUSION Availability, accuracy, cost, resource utilization, the requirement for one or multiple tests, safety, patient acceptability, and ease of implementation are among the important and sometimes competing factors to be considered when selecting noninvasive imaging options for the assessment of ischemia and viability. The level of complexity of clinical question may vary from a simple binary determination of the presence or absence of ischemia in single-vessel disease with preserved LV function to assessment of the optimal treatment strategy of a patient with multivessel disease and heart failure, integrating questions regarding the advisability of mitral valve repair or resynchronization therapy. At lower levels of clinical complexity, the differences in diagnostic accuracy between the invasive imaging modalities discussed play less of a role than availability and cost, which will vary from institution to institution. However, as the clinical questions to be answered become more complex and involved, perhaps necessitating the use of more than one imaging modality, and the cost implications of treatment decisions escalate, the superior diagnostic capabilities of CMR are set to make this technique the test of choice in the future.

jâ•… REFERENCES 1. Master A, Friedman R, Dach S. The electrocardiogram after standard exercise as a functional test of the heart. Am Heart J. 1942;24:777. 2. Rahimtoola SH. Coronary bypass surgery for chronic angina—1981. A perspective. Circulation. 1982;65(2):225–241. 3. Di Carli M, Czernin J, Hoh CK, et al. Relation among stenosis severity, myocardial blood flow, and flow reserve in patients with coronary artery disease. Circulation. 1995;91(7):1944–1951. 4. Brosh D, Higano ST, Lennon RJ, Holmes DR Jr, Lerman A. Effect of lesion length on fractional flow reserve in intermediate coronary lesions. Am Heart J. 2005;150(2):338–343. 5. Tennant R, Wiggers C. The effects of coronary occlusion on myocardial contraction. Am J Physiol. 1935;112:351. 6. Allman KC, Shaw LJ, Hachamovitch R, Udelson JE. Myocardial viability testing and impact of revascularization on prognosis in patients with coronary artery disease and left ventricular dysfunction: a meta-analysis. J Am Coll Cardiol. 2002;39(7):1151–1158. 7. Heusch G, Schulz R, Rahimtoola SH. Myocardial hibernation: a delicate balance. Am J Physiol Heart Circ Physiol. 2005;288(3):H984–H999. 8. Panting JR, Gatehouse PD, Yang GZ, et al. Abnormal subendocardial perfusion in cardiac syndrome X detected by cardiovascular magnetic resonance imaging. N Engl J Med. 2002;346(25):1948–1953. 9. Cecchi F, Olivotto I, Gistri R, Lorenzoni R, Chiriatti G, Camici PG. Coronary microvascular dysfunction and prognosis in hypertrophic cardiomyopathy. N Engl J Med. 2003;349(11):1027–1035. 10. Rieber J, Huber A, Erhard I, et al. Cardiac magnetic resonance perfusion imaging for the functional assessment of coronary artery disease: a comparison with coronary angiography and fractional flow reserve. Eur Heart J. 2006;27(12):1465–1471. 11. Hauser A, Vellappillil G, Ramos R, et al. Sequence of mechanical, electro-cardiographic and clinical effects of repeated coronary artery occlusion in human beings: echocardiographic observations during coronary angioplasty. J Am Coll Cardiol. 1985;5:193–197. 12. Nesto R, Kowalchuk G. The ischemic cascade: temporal sequence of hemodynamic, electrocardiographic and symptomatic expressions of ischemia. Am J Cardiol. 1987;57:23C–30C.

Multimodality Imaging in Cardiovascular Medicine

13. Leong-Poi H, Rim SJ, Le DE, Fisher NG, Wei K, Kaul S. Perfusion versus function: the ischemic cascade in demand ischemia: implications of single-vessel versus multivessel stenosis. Circulation. 2002;105(8):987–992. 14. Gianrossi R, Detrano R, Mulvihill D, et al. Exercise-induced ST depression in the diagnosis of coronary artery disease: a meta-analysis. Circulation. 1989;80(1):87–98. 15. Gibbons RJ, Balady GJ, Bricker JT, et al. ACC/AHA 2002 guideline update for exercise testing: summary article. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1997 Exercise Testing Guidelines). J Am Coll Cardiol. 2002;40(8):1531–1540. 16. Zaret BL, Stenson RE, Martin ND, et al. Potassium-43 myocardial perfusion scanning for the noninvasive evaluation of patients with false-positive exercise tests. Circulation. 1973;48(6):1234–1241. 17. Zaret BL, Strauss HW, Martin ND, Wells HP Jr, Flamm MD Jr. Noninvasive regional myocardial perfusion with radioactive potassium. Study of patients at rest, with exercise and during angina pectoris. N Engl J Med. 1973;288(16):809–812. 18. Strauss HW, Harrison K, Langan JK, Lebowitz E, Pitt B. Thallium-201 for myocardial imaging. Relation of thallium-201 to regional myocardial perfusion. Circulation. 1975;51(4):641–645. 19. Taillefer R, DePuey EG, Udelson JE, Beller GA, Latour Y, Reeves F. Comparative diagnostic accuracy of Tl-201 and Tc-99m sestamibi SPECT imaging (perfusion and ECG-gated SPECT) in detecting coronary artery disease in women. J Am Coll Cardiol. 1997;29(1):69–77. 20. Dilsizian V, Rocco TP, Freedman NM, Leon MB, Bonow RO. Enhanced detection of ischemic but viable myocardium by the reinjection of thallium after stress-redistribution imaging. N Engl J Med. 1990;323(3):141–146. 21. Frans J, Wackers F. SPECT detection of coronary artery disease. In: Dilsizian V, Narula J, eds., Atlas of Nuclear Cardiology. Philadelphia, PA: Current Medicine; 2003:63–77. 22. Yoshinaga K, Chow BJW, Williams K, et al. What is the prognostic value of myocardial perfusion imaging using Rubidium-82 positron emission tomography? J Am Coll Cardiol. 2006;48(5):1029–1039. 23. Cortigiani L, Picano E, Coletta C, et al. Safety, feasibility, and prognostic implications of pharmacologic stress echocardiography in 1482 patients evaluated in an ambulatory setting. Am Heart J. 2001;141(4):621–629. 24. Dodi C, Cortigiani L, Masini M, Olivotto I, Azzarelli A, Nannini E. The incremental prognostic value of pharmacological stress echo over exercise electrocardiography in women with chest pain of unknown origin. Eur Heart J. 2001;22(2):145–152. 25. Geleijnse ML, Fioretti PM, Roelandt JR. Methodology, feasibility, safety and diagnostic accuracy of dobutamine stress echocardiography. J Am Coll Cardiol. 1997;30(3):595–606. 26. Ho YL, Wu CC, Huang PJ, et al. Assessment of coronary artery disease in women by dobutamine stress echocardiography: comparison with stress thallium-201 single-photon emission computed tomography and exercise electrocardiography. Am Heart J. 1998;135(4):655–662. 27. Madler CF, Payne N, Wilkenshoff U, et al. Non-invasive diagnosis of coronary artery disease by quantitative stress echocardiography: optimal diagnostic models using off-line tissue Doppler in the MYDISE study. Eur Heart J. 2003;24(17):1584–1594. 28. Marwick TH. Current status of stress echocardiography for diagnosis and prognostic assessment of coronary artery disease. Coron Artery Dis. 1998;9(7):411–426. 29. Marwick TH, Anderson T, Williams MJ, et al. Exercise echocardiography is an accurate and cost-efficient technique for detection of coronary artery disease in women. J Am Coll Cardiol. 1995;26(2):335–341. 30. Marwick TH, Mehta R, Arheart K, Lauer MS. Use of exercise echocardiography for prognostic evaluation of patients with known or suspected coronary artery disease. J Am Coll Cardiol. 1997;30(1):83–90. 31. Marwick TH, Shaw LJ, Lauer MS, et al. The noninvasive prediction of cardiac mortality in men and women with known or suspected

C HA P TER 10

•

Chronic Myocardial Ischemia and Viability

coronary artery disease. Economics of Noninvasive Diagnosis (END) Study Group. Am J Med. 1999;106(2):172–178. 32. Secknus MA, Marwick TH. Evolution of dobutamine echocardiography protocols and indications: safety and side effects in 3011 studies over 5 years. J Am Coll Cardiol. 1997;29(6):1234–1240. 33. Picano E, Molinaro S, Pasanisi E. The diagnostic accuracy of pharmacological stress echocardiography for the assessment of coronary artery disease: a meta-analysis. Cardiovasc Ultrasound. 2008;6:30. 34. Picano E, Bedetti G, Varga A, Cseh E. The comparable diagnostic accuracies of dobutamine-stress and dipyridamole-stress echocardiographies: a meta-analysis. Coron Artery Dis. 2000;11(2):151–159. 35. Heijenbrok-Kal MH, Fleischmann KE, Hunink MG. Stress echocardiography, stress single-photon-emission computed tomography and electron beam computed tomography for the assessment of coronary artery disease: a meta-analysis of diagnostic performance. Am Heart J. 2007;154(3):415–423. 36. Cheitlin MD, Armstrong WF, Aurigemma GP, et al. ACC/AHA/ ASE 2003 guideline update for the clinical application of echocardiography: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/ASE Committee to Update the 1997 Guidelines for the Clinical Application of Echocardiography). Circulation. 2003;108(9):1146–1162. 37. Cain P, Marwick TH, Case C, et al. Assessment of regional long-axis function during dobutamine echocardiography. Clin Sci (Lond). 2001;100(4):423–432. 38. Davidavicius G, Kowalski M, Williams RI, et al. Can regional strain and strain rate measurement be performed during both dobutamine and exercise echocardiography, and do regional deformation responses differ with different forms of stress testing? J Am Soc Echocardiogr. 2003;16(4):299–308. 39. Marwick TH, Case C, Leano R, et al. Use of tissue Doppler imaging to facilitate the prediction of events in patients with abnormal left ventricular function by dobutamine echocardiography. Am J Cardiol. 2004;93(2):142–146. 40. Varnero S, Santagata P, Pratali L, Basso M, Gandolfo A, Bellotti P. Head to head comparison of 2D vs real time 3D dipyridamole stress echocardiography. Cardiovasc Ultrasound. 2008;6:31. 41. Takeuchi M, Otani S, Weinert L, Spencer KT, Lang RM. Comparison of contrast-enhanced real-time live 3-dimensional dobutamine stress echocardiography with contrast 2-dimensional echocardiography for detecting stress-induced wall-motion abnormalities. J Am Soc Echocardiogr. 2006;19(3):294–299. 42. Korosoglou G, Dubart AE, DaSilva KG Jr, et al. Real-time myocardial perfusion imaging for pharmacologic stress testing: added value to single photon emission computed tomography. Am Heart J. 2006;151(1):131–138. 43. Abe Y, Muro T, Sakanoue Y, et al. Intravenous myocardial contrast echocardiography predicts regional and global left ventricular remodelling after acute myocardial infarction: comparison with low dose dobutamine stress echocardiography. Heart. 2005;91(12):1578–1583. 44. Meimoun P, Benali T, Sayah S, et al. Evaluation of left anterior descending coronary artery stenosis of intermediate severity using transthoracic coronary flow reserve and dobutamine stress echocardiography. J Am Soc Echocardiogr. 2005;18(12):1233–1240. 45. Meimoun P, Tribouilloy C. Non-invasive assessment of coronary flow and coronary flow reserve by transthoracic Doppler echocardiography: a magic tool for the real world. Eur J Echocardiogr. 2008;9(4):449–457. 46. Pennell DJ, Underwood SR, Manzara CC, et al. Magnetic resonance imaging during dobutamine stress in coronary artery disease. Am J Cardiol. 1992;70(1):34–40. 47. Nandalur KR, Dwamena BA, Choudhri AF, Nandalur MR, Carlos RC. Diagnostic performance of stress cardiac magnetic resonance imaging in the detection of coronary artery disease: a meta-analysis. J Am Coll Cardiol. 2007;50(14):1343–1353. 48. Edvardsen T, Gerber BL, Garot J, Bluemke DA, Lima JA, Smiseth OA. Quantitative assessment of intrinsic regional myocardial Â�deformation by Doppler strain rate echocardiography in humans:

155

49.

50.

51.

52.

53.

54.

55.

56.

57.

58.

59.

60.

61.

62.

63.

64.

65.

66.

validation against three-dimensional tagged magnetic resonance imaging. Circulation. 2002;106(1):50–56. Kuijpers D, Ho KY, van Dijkman PR, Vliegenthart R, Oudkerk M. Dobutamine cardiovascular magnetic resonance for the detection of myocardial ischemia with the use of myocardial tagging. Circulation. 2003;107(12):1592–1597. Rerkpattanapipat P, Gandhi SK, Darty SN, et al. Feasibility to detect severe coronary artery stenoses with upright treadmill exercise magnetic resonance imaging. Am J Cardiol. 2003;92(5):603–606. Pennell DJ, Underwood SR, Ell PJ, Swanton RH, Walker JM, Longmore DB. Dipyridamole magnetic resonance imaging: a comparison with thallium-201 emission tomography. Br Heart J. 1990;64(6):362–369. Paetsch I, Jahnke C, Wahl A, et al. Comparison of dobutamine stress magnetic resonance, adenosine stress magnetic resonance, and adenosine stress magnetic resonance perfusion. Circulation. 2004;110(7):835–842. Bodi V, Sanchis J, Lopez-Lereu MP, et al. Prognostic value of dipyridamole stress cardiovascular magnetic resonance imaging in patients with known or suspected coronary artery disease. J Am Coll Cardiol. 2007;50(12):1174–1179. Nagel E, Lehmkuhl HB, Bocksch W, et al. Noninvasive diagnosis of ischemia-induced wall motion abnormalities with the use of highdose dobutamine stress MRI: comparison with dobutamine stress echocardiography. Circulation. 1999;99(6):763–770. Hundley WG, Hamilton CA, Thomas MS, et al. Utility of fast cine magnetic resonance imaging and display for the detection of myocardial ischemia in patients not well suited for second harmonic stress echocardiography. Circulation. 1999;100(16):1697–1702. Hundley WG, Morgan TM, Neagle CM, Hamilton CA, Rerkpattanapipat P, Link KM. Magnetic resonance imaging determination of cardiac prognosis. Circulation. 2002;106(18):2328–2333. Heidemann RM, Ozsarlak O, Parizel PM, et al. A brief review of parallel magnetic resonance imaging. Eur Radiol. 2003;13(10): 2323–2337. Tong CY, Prato FS, Wisenberg G, et al. Measurement of the extraction efficiency and distribution volume for Gd-DTPA in normal and diseased canine myocardium. Magn Reson Med. 1993;30(3):337–346. Wilke N, Kroll K, Merkle H, et al. Regional myocardial blood volume and flow: first-pass MR imaging with polylysine-Gd-DTPA. J Magn Reson Imaging. 1995;5(2):227–237. Giang TH, Nanz D, Coulden R, et al. Detection of coronary artery disease by magnetic resonance myocardial perfusion imaging with various contrast medium doses: first European multi-centre experience. Eur Heart J. 2004;25(18):1657–1665. Cerqueira MD, Verani MS, Schwaiger M, Heo J, Iskandrian AS. Safety profile of adenosine stress perfusion imaging: results from the Adenoscan Multicenter Trial Registry. J Am Coll Cardiol. 1994;23(2):384–389. Schwitter J, Debatin JF, von Schulthess GK, McKinnon GC. Normal myocardial perfusion assessed with multishot echo-planar imaging. Magn Reson Med 1997;37(1):140–147. Plein S, Greenwood JP, Ridgway JP, Cranny G, Ball SG, Sivananthan MU. Assessment of non-ST-segment elevation acute coronary syndromes with cardiac magnetic resonance imaging. J Am Coll Cardiol. 2004;44(11):2173–2181. Takase B, Nagata M, Kihara T, et al. Whole-heart dipyridamole stress first-pass myocardial perfusion MRI for the detection of Â�coronary artery disease. Jpn Heart J. 2004;45(3):475–486. Cerqueira MD, Weissman NJ, Dilsizian V, et al. Standardized myocardial segmentation and nomenclature for tomographic imaging of the heart: a statement for healthcare professionals from the Cardiac Imaging Committee of the Council on Clinical Cardiology of the American Heart Association. J Nucl Cardiol. 2002;9(2):240–245. Schwitter J, Nanz D, Kneifel S, et al. Assessment of myocardial perfusion in coronary artery disease by magnetic resonance: a comparison with positron emission tomography and coronary angiography. Circulation. 2001;103(18):2230–2235.

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67. Al-Saadi N, Nagel E, Gross M, et al. Noninvasive detection of myocardial ischemia from perfusion reserve based on cardiovascular magnetic resonance. Circulation. 2000;101(12):1379–1383. 68. Nagel E, Klein C, Paetsch I, et al. Magnetic resonance perfusion measurements for the noninvasive detection of coronary artery disease. Circulation. 2003;108(4):432–437. 69. Jerosch-Herold M, Wilke N, Stillman AE. Magnetic resonance quantification of the myocardial perfusion reserve with a Fermi function model for constrained deconvolution. Med Phys. 1998;25(1):73–84. 70. Larsson HB, Stubgaard M, Sondergaard L, Henriksen O. In vivo quantification of the unidirectional influx constant for Gd-DTPA diffusion across the myocardial capillaries with MR imaging. J Magn Reson Imaging. 1994;4(3):433–440. 71. Hsu LY, Rhoads KL, Holly JE, Kellman P, Aletras AH, Arai AE. Quantitative myocardial perfusion analysis with a dual-bolus Â�contrast-enhanced first-pass MRI technique in humans. J Magn Reson Imaging. 2006;23(3):315–322. 72. Christian TF, Rettmann DW, Aletras AH, et al. Absolute myocardial perfusion in canines measured by using dual-bolus first-pass MR imaging. Radiology. 2004;232(3):677–684. 73. Gatehouse PD, Elkington AG, Ablitt NA, Yang GZ, Pennell DJ, Firmin DN. Accurate assessment of the arterial input function during high-dose myocardial perfusion cardiovascular magnetic resonance. J Magn Reson Imaging. 2004;20(1):39–45. 74. Elkington AG, He T, Gatehouse PD, Prasad SK, Firmin DN, Pennell DJ. Optimization of the arterial input function for myocardial perfusion cardiovascular magnetic resonance. J Magn Reson Imaging. 2005;21(4):354–359. 75. Kim D, Axel L. Multislice, dual-imaging sequence for increasing the dynamic range of the contrast-enhanced blood signal and CNR of myocardial enhancement at 3T. J Magn Reson Imaging. 2006;23(1):81–86. 76. Manning WJ, Atkinson DJ, Grossman W, Paulin S, Edelman RR. First-pass nuclear magnetic resonance imaging studies using Â�gadolinium-DTPA in patients with coronary artery disease. J Am Coll Cardiol. 1991;18(4):959–965. 77. Ishida N, Sakuma H, Motoyasu M, et al. Noninfarcted myocardium: correlation between dynamic first-pass contrast-enhanced myocardial MR imaging and quantitative coronary angiography. Radiology. 2003;229(1):209–216. 78. Pilz G, Bernhardt P, Klos M, Ali E, Wild M, Hofling B. Clinical implication of adenosine-stress cardiac magnetic resonance imaging as potential gatekeeper prior to invasive examination in patients with AHA/ACC class II indication for coronary angiography. Clin Res Cardiol. 2006;95(10):531–538. 79. Schwitter J, Wacker CM, van Rossum AC, et al. MR-IMPACT: Â�comparison of perfusion-cardiac magnetic resonance with singlephoton emission computed tomography for the detection of coronary artery disease in a multicentre, multivendor, randomized trial. Eur Heart J. 2008;29(4):480–489. 80. Schwitter J. Myocardial perfusion imaging by cardiac magnetic resonance. J Nucl Cardiol. 2006;13(6):841–854. 81. Fearon WF, Tonino PA, De Bruyne B, Siebert U, Pijls NH. Rationale and design of the fractional flow reserve versus angiography for multivessel evaluation (FAME) study. Am Heart J. 2007;154(4):632–636. 82. Pijls NH, van Schaardenburgh P, Manoharan G, et al. Percutaneous coronary intervention of functionally nonsignificant stenosis: 5-year follow-up of the DEFER Study. J Am Coll Cardiol. 2007;49(21):2105–2111. 83. Ingkanisorn WP, Kwong RY, Bohme NS, et al. Prognosis of negative adenosine stress magnetic resonance in patients presenting to an emergency department with chest pain. J Am Coll Cardiol. 2006;47(7):1427–1432. 84. Pilz G, Jeske A, Klos M, et al. Prognostic value of normal Â�adenosine-stress cardiac magnetic resonance imaging. Am J Cardiol. 2008;101(10):1408–1412.

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85. Jahnke C, Nagel E, Gebker R, et al. Prognostic value of cardiac magnetic resonance stress tests: adenosine stress perfusion and dobutamine stress wall motion imaging. Circulation. 2007;115(13):1769–1776. 86. Hendel RC, Patel MR, Kramer CM, et al. ACCF/ACR/SCCT/SCMR/ ASNC/NASCI/SCAI/SIR 2006 appropriateness criteria for cardiac computed tomography and cardiac magnetic resonance imaging: a report of the American College of Cardiology Foundation Quality Strategic Directions Committee Appropriateness Criteria Working Group, American College of Radiology, Society of Cardiovascular Computed Tomography, Society for Cardiovascular Magnetic Resonance, American Society of Nuclear Cardiology, North American Society for Cardiac Imaging, Society for Cardiovascular Angiography and Interventions, and Society of Interventional Radiology. J Am Coll Cardiol. 2006;48(7):1475–1497. 87. Cheng AS, Pegg TJ, Karamitsos TD, et al. Cardiovascular magnetic resonance perfusion imaging at 3-tesla for the detection of coronary artery disease: a comparison with 1.5-tesla. J Am Coll Cardiol. 2007;49(25):2440–2449. 88. Plein S, Kozerke S, Suerder D, et al. High spatial resolution myocardial perfusion cardiac magnetic resonance for the detection of coronary artery disease. Eur Heart J. 2008. 89. Croisille P, Revel D, Saeed M. Contrast agents and cardiac MR imaging of myocardial ischemia: from bench to bedside. Eur Radiol. 2006;16(9):1951–1963. 90. Krombach GA, Higgins CB, Chujo M, Saeed M. Gadomer-enhanced MR imaging in the detection of microvascular obstruction: alleviation with nicorandil therapy. Radiology. 2005;236(2):510–518. 91. Peukert D, Kaufels N, Laule M, et al. Improved evaluation of myocardial perfusion and viability with the magnetic resonance blood pool contrast agent p792 in a nonreperfused porcine infarction model. Invest Radiol. 2007;42(4):248–255. 92. Kannel WB. Lessons from curbing the coronary artery disease epidemic for confronting the impending epidemic of heart failure. Med Clin North Am. 2004;88(5):1129–1133, ix. 93. Gheorghiade M, Bonow RO. Chronic heart failure in the United States: a manifestation of coronary artery disease. Circulation. 1998;97(3):282–289. 94. Di Carli MF, Asgarzadie F, Schelbert HR, et al. Quantitative relation between myocardial viability and improvement in heart failure symptoms after revascularization in patients with ischemic cardiomyopathy. Circulation. 1995;92(12):3436–3444. 95. Dilsizian V, Bonow RO. Differential uptake and apparent 201Tl washout after thallium reinjection. Options regarding early redistribution imaging before reinjection or late redistribution imaging after reinjection. Circulation. 1992;85(3):1032–1038. 96. Underwood SR, Bax JJ, vom Dahl J, et al. Imaging techniques for the assessment of myocardial hibernation. Report of a Study Group of the European Society of Cardiology. Eur Heart J. 2004;25(10):815–836. 97. Dilsizian V, Arrighi JA, Diodati JG, et al. Myocardial viability in patients with chronic coronary artery disease. Comparison of 99m Tc-sestamibi with thallium reinjection and [18F]fluorodeoxyglucose. Circulation. 1994;89(2):578–587. 98. Caner B, Beller GA. Are technetium-99m-labeled myocardial perfusion agents adequate for detection of myocardial viability? Clin Cardiol. 1998;21(4):235–242. 99. Roelants V, Bernard X, Walrand S, et al. Attenuation-corrected 99m Tc-MIBI SPECT in overweight patients with chronic ischaemic dysfunction: a comparison to NH3 PET and implications for the diagnosis of myocardial viability. Nucl Med Commun. 2006;27(10):815–821. 100. Bax JJ, Poldermans D, Elhendy A, Boersma E, Rahimtoola SH. Sensitivity, specificity, and predictive accuracies of various noninvasive techniques for detecting hibernating myocardium. Curr Probl Cardiol. 2001;26(2):147–186. 101. Wijns W, Vatner SF, Camici PG. Hibernating myocardium. N Engl J Med. 1998;339(3):173–181.

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102. Afridi I, Grayburn PA, Panza JA, Oh JK, Zoghbi WA, Marwick TH. Myocardial viability during dobutamine echocardiography predicts survival in patients with coronary artery disease and severe left ventricular systolic dysfunction. J Am Coll Cardiol. 1998;32(4):921–926. 103. Panza JA, Dilsizian V, Laurienzo JM, Curiel RV, Katsiyiannis PT. Relation between thallium uptake and contractile response to dobutamine. Implications regarding myocardial viability in patients with chronic coronary artery disease and left ventricular dysfunction. Circulation. 1995;91(4):990–998. 104. Barrington SF, Chambers J, Hallett WA, O’Doherty MJ, Roxburgh JC, Nunan TO. Comparison of sestamibi, thallium, echocardiography and PET for the detection of hibernating myocardium. Eur J Nucl Med Mol Imaging. 2004;31(3):355–361. 105. Hoffmann R. Tissue Doppler and innovative myocardial-Â�deformation imaging techniques for assessment of myocardial viability. Curr Opin Cardiol. 2006;21(5):438–442. 106. Kim RJ, Fieno DS, Parrish TB, et al. Relationship of MRI delayed contrast enhancement to irreversible injury, infarct age, and contractile function. Circulation. 1999;100(19):1992–2002. 107. Schinkel AFL, Poldermans D, Elhendy A, Bax JJ. Assessment of myocardial viability in patients with heart failure. J Nucl Med. 2007;48(7):1135–1146. 108. Schinkel AF, Bax JJ, Boersma E, et al. Assessment of residual myocardial viability in regions with chronic electrocardiographic Q-wave infarction. Am Heart J. 2002;144(5):865–869. 109. Baer FM, Voth E, Schneider CA, Theissen P, Schicha H, Sechtem U. Comparison of low-dose dobutamine-gradient-echo magnetic resonance imaging and positron emission tomography with [18F]fluorodeoxyglucose in patients with chronic coronary artery disease. A functional and morphological approach to the detection of residual myocardial viability. Circulation. 1995;91(4):1006–1015. 110. Baer FM, Theissen P, Schneider CA, et al. Dobutamine magnetic resonance imaging predicts contractile recovery of chronically dysfunctional myocardium after successful revascularization. J Am Coll Cardiol. 1998;31(5):1040–1048. 111. Wellnhofer E, Olariu A, Klein C, et al. Magnetic resonance low-dose dobutamine test is superior to SCAR quantification for the prediction of functional recovery. Circulation. 2004;109(18):2172–2174. 112. Kim RJ, Manning WJ. Viability assessment by delayed enhancement cardiovascular magnetic resonance: will low-dose dobutamine dull the shine? Circulation. 2004;109(21):2476–2479. 113. Kaandorp TA, Lamb HJ, van der Wall EE, de Roos A, Bax JJ. Cardiovascular MR to access myocardial viability in chronic ischaemic LV dysfunction. Heart. 2005;91(10):1359–1365. 114. Simonetti OP, Kim RJ, Fieno DS, et al. An improved MR imaging technique for the visualization of myocardial infarction. Radiology. 2001;218(1):215–223. 115. Li W, Li BS, Polzin JA, Mai VM, Prasad PV, Edelman RR. Myocardial delayed enhancement imaging using inversion recovery single-shot steady-state free precession: initial experience. J Magn Reson Imaging. 2004;20(2):327–330. 116. Kellman P, Arai AE, McVeigh ER, Aletras AH. Phase-sensitive inversion recovery for detecting myocardial infarction using gadoliniumdelayed hyperenhancement. Magn Reson Med. 2002;47(2):372–383. 117. Peukert D, Laule M, Taupitz M, Kaufels N, Hamm B, Dewey M. 3D and 2D delayed-enhancement magnetic resonance imaging for detection of myocardial infarction: preclinical and clinical results. Acad Radiol. 2007;14(7):788–794. 118. Ibrahim el SH, Stuber M, Kraitchman DL, Weiss RG, Osman NF. Combined functional and viability cardiac MR imaging in a single breathhold. Magn Reson Med. 2007;58(4):843–849. 119. Ibrahim el SH, Weiss RG, Stuber M, et al. Stimulated-echo acquisition mode (STEAM) MRI for black-blood delayed hyperenhanced myocardial imaging. J Magn Reson Imaging. 2008;27(1):229–238. 120. Rehwald WG, Fieno DS, Chen E-L, Kim RJ, Judd RM. Myocardial magnetic resonance imaging contrast agent concentrations after reversible and irreversible ischemic injury. Circulation. 2002;105(2):224–229.

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121. Bulow H, Klein C, Kuehn I, et al. Cardiac magnetic resonance imaging: long term reproducibility of the late enhancement signal in patients with chronic coronary artery disease. Heart. 2005;91(9):1158–1163. 122. Ibrahim T, Nekolla SG, Hornke M, et al. Quantitative measurement of infarct size by contrast-enhanced magnetic resonance imaging early after acute myocardial infarction: comparison with singlephoton emission tomography using Tc99m-sestamibi. J Am Coll Cardiol. 2005;45(4):544–552. 123. Kwong RY, Chan AK, Brown KA, et al. Impact of unrecognized myocardial scar detected by cardiac magnetic resonance imaging on event-free survival in patients presenting with signs or symptoms of coronary artery disease. Circulation. 2006;113(23): 2733–2743. 124. Kwong RY, Sattar H, Wu H, et al. Incidence and prognostic implication of unrecognized myocardial scar characterized by cardiac magnetic resonance in diabetic patients without clinical evidence of myocardial infarction. Circulation. 2008;118(10):1011–1020. 125. Selvanayagam JB, Kardos A, Francis JM, et al. Value of delayedenhancement cardiovascular magnetic resonance imaging in predicting myocardial viability after surgical revascularization. Circulation. 2004;110(12):1535–1541. 126. Lauerma K, Niemi P, Hanninen H, et al. Multimodality MR imaging assessment of myocardial viability: combination of first-pass and late contrast enhancement to wall motion dynamics and comparison with FDG PET-initial experience. Radiology. 2000;217(3):729–736. 127. Bello D, Shah DJ, Farah GM, et al. Gadolinium cardiovascular magnetic resonance predicts reversible myocardial dysfunction and remodeling in patients with heart failure undergoing beta-blocker therapy. Circulation. 2003;108(16):1945–1953. 128. Bleeker GB, Kaandorp TA, Lamb HJ, et al. Effect of posterolateral scar tissue on clinical and echocardiographic improvement after cardiac resynchronization therapy. Circulation. 2006;113(7):969–976. 129. Wang L, Zhu HY, Tian JM, Huang SD, Kong LS, Lu JP. Magnetic resonance imaging in determination of myocardial ischemia and viability: comparison with positron emission tomography and single-photon emission computed tomography in a porcine model. Acta Radiol. 2007;48(5):500–507. 130. Kuhl HP, Lipke CS, Krombach GA, et al. Assessment of reversible myocardial dysfunction in chronic ischaemic heart disease: comparison of contrast-enhanced cardiovascular magnetic resonance and a combined positron emission tomography-single photon emission computed tomography imaging protocol. Eur Heart J. 2006;27(7):846–853. 131. Wagner A, Mahrholdt H, Sechtem U, Kim RJ, Judd RM. MR imaging of myocardial perfusion and viability. Magn Reson Imaging Clin N Am. 2003;11(1):49–66. 132. Klein C, Nekolla SG, Bengel FM, et al. Assessment of myocardial viability with contrast-enhanced magnetic resonance imaging: comparison with positron emission tomography. Circulation. 2002;105(2):162–167. 133. Schinkel AF, Poldermans D, Rizzello V, et al. Why do patients with ischemic cardiomyopathy and a substantial amount of viable myocardium not always recover in function after revascularization? J Thorac Cardiovasc Surg. 2004;127(2):385–390. 134. Schinkel AF, Poldermans D, Vanoverschelde JL, et al. Incidence of recovery of contractile function following revascularization in patients with ischemic left ventricular dysfunction. Am J Cardiol. 2004;93(1):14–17. 135. Westenberg JJ, Doornbos J, Versteegh MI, et al. Accurate quantitation of regurgitant volume with MRI in patients selected for mitral valve repair. Eur J Cardiothorac Surg. 2005;27(3):462–426, discussion 467. 136. Athanasuleas CL, Buckberg GD, Stanley AW, et al. Surgical ventricular restoration in the treatment of congestive heart failure due to post-infarction ventricular dilation. J Am Coll Cardiol. 2004;44(7):1439–1445.

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Multimodality Imaging in Valvular Heart Disease

So naL CHanDra Am iT R . PaTeL Lissa SUGenG

As medicine has evolved, clinicians have embraced contemporary methods to aid in the diagnosis and management of cardiac disease, specifically valvular heart disease. During the first half of the last century, rheumatic fever was the major cardiac health issue faced by physicians and was attributed as a cause of 20% of all heart diseases [1]. Epidemiologic studies, recognition of the causative organism, diagnosis based on symptoms along with inflammatory markers, public health solutions, and antibiotics were all major achievements of this era [2,3]. One of the most prominent physicians in the twentieth century, Paul Wood described clinical features, auscultatory findings, electrocardiographic manifestations, X-ray, and wedge pressure measurements of patients with mitral stenosis. The treatment of mitral stenosis, a result of rheumatic fever, was manual dilatation (finger fracture), which was first performed in the 1920s [4]. Inga Edler was particularly interested in determining the severity of mitral regurgitation (MR) prior to the procedure. Edler and Hertz were the first to record moving structures of the heart in 1953 [5]. It is during the second half of the twentieth century that we have made great strides in establishing accurate diagnosis of valvular heart disease using echocardiography and in understanding intracardiac hemodynamics with Doppler echocardiography. Echocardiography is ubiquitous in current cardiology practice due to its size and portability, absence of irradiation, and ease of use in initial diagnosis as well as for follow-up studies. With the development of extracorporeal circulation, open cardiac surgeries such as open commissurotomy, mitral valve (MV) replacement, and MV repair necessitated high-resolution imaging. Subsequent advances in ultrasound, miniaturization, and efficient electronics have enabled development of 2-dimensional (2D) transesophageal echocardiography (TEE) and most recently 3D matrix TEE (mTEE), thereby further facilitating ease and accuracy in preoperative diagnosis, surgical planning, intraoperative monitoring, and 15 8

postoperative evaluation [6–12]. With continued miniaturization of ultrasound units, smaller and improved probe technology, we can envision future use of hand-held echo units in our routine physical examinations not dissimilar to present use of pocket-held tools such as the stethoscope. Echocardiography is the dominant imaging modality for evaluation of patients with valvular heart disease, and the high spatial and temporal resolution achievable with echocardiography is unmatched in visualization of valve morphology. However, newer imaging techniques such as cardiac magnetic resonance imaging (CMR) and cardiac computed tomographic (CCT) evaluation of transvalvular flow abnormalities by combining morphologic and volumetric evaluation of the valve and its associated structures, are lending a better understanding to the timing of surgery in patients with valvular lesions. Currently, CCT or CMR play an adjunctive or alternative role to echocardiography and are used primarily when echocardiographic data is insufficient. However, CCT and magnetic resonance imaging (MRI) are usurping echocardiographic evaluation of valvular heart disease in instances such as congenital heart disease by becoming the initial and/or surveillance imaging modality of choice. The main strength of CMR is to provide quantitative regurgitant measurements in addition to precise quantification of ventricular adaptation to pressure and/or volume overload. CCT is gaining popularity as the modality of choice for further assessment of prosthetic valve abnormalities and preprocedural planning for percutaneous valve procedures. The goal of this chapter is to highlight the strengths, limitations, and current application of echocardiography, CMR, and CCT in the diagnosis and treatment of valve disease.

jâ•…M ITRAL VALVE The MV is a complex structure comprising of an annulus, two leaflets, numerous tendinous chordae, and two papillary muscles; and requires an integration of all of its components to function adequately. The MV also retains an important integrative relationship with the aortic valve, therefore, pathology in one whether intrinsic or iatrogenic has the potential to adversely influence another. There is a

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fibrous continuity between the anterior leaflet of the MV and the aortic valve. The posterior leaflet or the mural leaflet has 3 individual scallops named P1–P3, which move independently of one another. The anterior leaflet has similar nomenclature with segments (A1–A3) analogous to the posterior scallops. The anterior and posterior leaflets come together to form a concave line of closure best demonstrated in atrial views of the MV by 3D echocardiography (3DE) (Figure 11.1). The annulus which gives rise to the leaflets was initially described by Gross and Kugel as having considerable variation in its extent, distribution, and connections with the various leaflet cusps [6]. Its composition varies from a fibrous tissue ring to a curtainlike separation between the mitral and the aortic valves. The tendinous chordae originating from the papillary muscles and infrequently from posterior ventricular wall, insert with some variation into the leaflets and the commissures. The detailed description by Lam et al on chordal morphology and site of attachment has lent considerable insight into the potential functional significance of restricted or ruptured chords [7]. Papillary muscles anchor the mitral apparatus and maintain appropriate tensile forces to preserve appropriate closure of the leaflets. They are usually situated anterolaterally and posteromedially, but are varied in the number of heads, size, and coronary supply. Imaging the entire MV apparatus is vital to the assessment of the malformations responsible for

the mechanistic derangement and subsequently, the reparative endeavors undertaken to restore them. Mitral Stenosis The primary cause of mitral stenosis (MS) is rheumatic fever, but it may be secondary to other etiologies as listed in Table 11.1. While the incidence of mitral stenosis resulting from rheumatic fever is declining in the western world, it remains substantially prevalent in the rest of the world. Despite the lack of difference in susceptibility to rheumatic fever between men and women, it is a disease process that affects women twice as often as men. Other than senile or nephrogenic calcification of MV, other uncommon causes of MS include carcinoid heart disease, anorectic drugs, systematic lupus erythematosus, endomyocardial fibrosis, atrial myxoma, and mechanical valve thrombosis.

Echocardiography The diagnosis and first surgical intervention of MS were achieved without visualization of the MV. Valvular regurgitation as a result of digital fracture of the mitral commissures was not anticipated. Though auscultation may provide us with the diagnosis and maybe for the expert auscultator, the degree of stenosis, echocardiography identifies and evaluates severity of disease, coexistent MR, as well as excludes conditions mimicking mitral stenosis. Additionally, it offers anatomic details on the thickness, mobility, degree of calcification, and fibrosis of the mitral apparatus, which have been proven to be useful in predicting the success of percutaneous mitral balloon valvuloplasty (PMBV) [8]. Wilkins score, a scoring system, comprised from the above-mentioned morphological features, is a rough estimate for suitability of PMBV. Although not included in the score, the symmetry and degree of the commissural fusion are also important toward determining surgical versus percutaneous approach. M-mode echocardiography is an ice-pick view of the heart that is still used to measure cavity dimensions and wall thickness [9,10]. The M-mode cursor is typically a straight line from the top of the ultrasound sector which, depending on the position of the probe relative to the heart, may jâ•… Table 11.1â•… Etiologies of mitral stenosis

F I G U R E 1 1 . 1 â•… Systematic 2-dimensional (2D) transesophageal echo-

cardiography (TEE) evaluation of the mitral valve. 2D TEE images were obtained in a midesophageal window at 0, 60, 90, and 130 degrees (A–D). 3D volume-rendered TEE image of the mitral valve (MV). White lines represent the approximate cut planes from which the respective 2D TEE images in panels A–D were obtained (E). In diastole, the MV indentations are more evident enabling identification of the posterior scallops (F).

159

• Rheumatic fever • Congenital malformation • Systemic carcinoid • Systemic lupus erythematosus • Rheumatoid arthritis • Mucopolysaccharidosis (Hunter syndrome, Hurler syndrome, Fabry disease, Whipple’s disease) • Amyloidosis • Pharmacologic agents (Fen/Phen therapy, methysergide) • Degenerative calcific disease

Multimodality Imaging in Cardiovascular Medicine

16 0

underestimate or overestimate left ventricular measurements. Alternatively, an anatomic M-mode (available on only certain systems) allows positioning of the cursor independent of the heart’s orientation. The use of M-mode in valvular heart disease is currently limited; nevertheless, one should be able to recognize the usual pattern of mitral stenosis (Figure 11.2A) consisting of restricted anterior leaflet motion causing a flattened and prolonged E-F slope. Quantitative methods to estimate the severity of mitral stenosis consist of the following 2D and Doppler echocardiographic parameters depicted in Figure 11.2B–F: the mean transmitral gradient obtained by tracing the mitral spectral envelope, MV area calculated by the pressure half-time (MVA 5 220/PHT) method, flow convergence or proximal isovelocity surface area (PISA) method, the continuity equation, and by 2D planimetry of the valve orifice. Mitral stenosis severity is determined by a combination of auscultation, MV area calculation by utilizing one or more of the above-mentioned techniques, and the transmitral gradient (Table 11.2). Although the mean gradient is easy to acquire and correlates well with cardiac catheterization data, Doppler spectral

envelope tracing performed on laminar flow could be variable under the influence of heart rate, atrial fibrillation, and concomitant MR [9]. The PHT method measures the time required for the peak gradient to fall to half of its peak value. Once the mitral area is 1 cm2, it takes 220 milliseconds for the peak transmitral gradient to decrease by half [10]. Factors affecting this measurement include changes in compliance of the left atrium or ventricle, severe aortic regurgitation or MR, cardiac function, and atrial arrhythmia or tachycardia [11,12]. The continuity equation, which is used to derive the MV area by measuring the left ventricular outflow tract (LVOT) velocity time integral (VTI), the LVOT area calculated from its diameter, and MV VTI using continuous-wave Doppler, is based on the conservation of mass and energy. However, it too is imperfect in the setting of concomitant aortic regurgitation or MR; is based on assumptions that the LVOT is a circle, and subject to inconsistent and poorly visualized measurements of the LVOT diameter [13,14]. Flow convergence or PISA method is also based on the conservation of mass and assumes that flow converging toward a horizontal orifice forms concentric, hemispheric, axisymmetric layers that are equal to the flow in the orifice. Flow is calculated at a particular hemispheric layer from the product of the aliasing velocity and the area of the hemisphere [15]. In the case of mitral stenosis, correction of the valve orifice angle is necessary since the line of coaptation is not necessarily a straight horizontal surface. Although the flow convergence technique demonstrates good correlation with planimetry and is uninfluenced by MR, it is limited by geometric assumptions regarding the shape of PISA, operator dependency of the color shift, and by the mitral leaflet angle [16,17]. Finally planimetry, a purely 2D measurement directly made from zoomed image of the MV in short-axis during diastasis by tracing the inside border of the mitral orifice, has correlated well with invasive catheterization measurements derived from the Gorlin formula [18]. However, improper placement of the imaging plane, higher gain settings, calcification, and mitral commissurotomy can all attribute to imprecise measurement of the MV area. 3DE has also been validated as a technique for estimation of MV area, when compared to conventional 2D and Gorlin-derived area calculations, which served previously as a reference method [18–21]. More recently, realtime 3D echocardiography (RT3DE) using a fully sampled mTEE probe has demonstrated better accuracy compared jâ•… Table 11.2â•… Mitral stenosis severity A2-OS interval (ms)

F I G U R E 1 1 . 2 â•…Echocardiographic detection and quantitation of mitral stenosis. (A) M-mode tracing. (B) Two-dimensional echocardiography (2DE) (parasternal long-axis and short-axis view). (C) Flow convergence. (D) Continuous-wave Doppler. (E) Volumetric 3DE of mitral stenosis from a left atrial perspective on the left and a left ventricular view on the right. (F) Multiplanar reconstruction (MPR) from a 3DE volume data demonstrating planimetry of the mitral valve orifice.

Area (cm2)

Gradient (mm Hg)

Mild

.110

.1.5

,5

Moderate

80–110

.1–15

5–10

Severe

,80

,1

.10

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to 2D planimetry and PHT-derived MVA, suggesting that 3DE should be considered the new clinical standard for the measurement of MV area in those with rheumatic mitral stenosis [22–24]. The advantages of the current RT3DE method include dramatic reduction in acquisition time, online display and review facilitated by the immediate en face visualization of the MV apparatus from the left atrium and left ventricle, as depicted in Figure 11.1E. 3DE is performed by using multiplanar views; an exact cutting plane is placed at the tips of the mitral leaflets in 2 orthogonal views producing an accurate short-axis cut plane of the MV orifice area (Figure 11.1F). Besides assessing feasibility and safety of performing percutaneous mitral balloon valvotomy (PMBV), 3DE does not underestimate the extent of commissural splitting post-valvuloplasty, a drawback of 2-dimensional echocardiography (2DE). Availability of online assessment of the MV area immediately after PBMV is convenient and allows for more accurate measurements to be performed independent of hemodynamics [24]. In 2007, a fully sampled 3D mTEE probe was developed with capability for instantaneous on-line display of cardiac anatomy. With its higher resolution and intraprocedural appraisal capability after balloon inflation, 3D mTEE has opened a more reproducible and accurate avenue for assessing the success of PBMV, as demonstrated in Figure 11.3A–C. A growing cause of mitral stenosis is degenerative mitral annular calcification (MAC) due to senile calcification, radiation, or chronic kidney disease [24–28]. Initial studies focusing on this disease entity used 2DE to merely detect the presence of calcification, but more recently it has been semiquantitated to determine the severity of calcification [28,29]. The degree of calcification is associated with inflammatory markers such as C-reactive protein, reduced left ventricular function, length of dialysis, and serves as a predictor of chronic kidney disease, particularly in diabetics [30–32]. Those with significant MAC have been associated with increased mortality and coronary artery disease [32,33]. 2DE is an easy initial screening

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tool for MAC, but RT3DE and CCT are more accurate tools for its quantification (Figure 11.4) [34].

Cardiac Magnetic Resonance Imaging CMR, which has the advantage of freedom from ionizing radiation and unrestricted anatomical access, is a uniquely versatile modality for the evaluation of valvular heart disease in adults. Valvular assessment in general by cardiac MRI involves the use of the following standard sequences: cine gradient-echo or steady-state free-precession (SSFP) to demonstrate wall motion, ventricular function, valve morphology, visualization of flow jets, and cine velocity–Â� encoded sequences for quantification of transvalvular regurgitant flow or peak velocities. Additional imaging dictated by specific clinical scenarios may consist of magnetic resonance angiography or utilization of late gadolinium enhancement imaging. While quantitative assessment by MRI is reliable, one must be aware of the potential errors inherent or introduced into the technique. Visualization of the valves by CMR depends on its location. The valve components with the highest diagnostic clarity score are tricuspid and MV annuli, leaflets and papillary muscles, and aortic valve annuli and leaflets. Chordae are properly visualized in only a minority of cases. In mitral stenosis, CMR via planimetry and phase-Â� contrast velocity encoding offers a noninvasive evaluation of valvular stenosis, which is independent of loading conditions. Qualitative indicators of a stenotic valve on MRI include restricted MV leaflet opening and presence of turbulent flow resulting in a signal void. Slices perpendicular to the valvular plane spanning from the annulus to leaflet tip, and in cases of orifices with an eccentric outlet, perpendicular to the origin of the jet, are used to planimeter the MV orifice. The most apical slice at maximal opening is measured. While there is a strong correlation with echocardiography and cardiac catheterization, there is a slight overestimation of MVA by CMR

F I G U R E 1 1 . 3 â•…A 3-dimensional transesophageal echocardiography volume-rendered image of a stenosed mitral valve (MV). (A) Pre-PBMV: the

MV is shown from a left atrial perspective. The medial and lateral commissures are fused. (B) Balloon inflation (white arrow). (C) Post-PBMV: the mitral valve is slightly more stretched without splitting the commissures (AV-aortic valve, Med-medial).

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planimetry, which can be attributed to imprecise localization of slices or transplanar valve motion [35]. Velocity-encoded MRI measurements of transmitral velocity in patients with mitral stenosis has acceptable level of agreement with echocardiographic continuouswave Doppler measurements across the MV [36]. Another parameter to assess MV stenosis is the PHT, which can also be extracted from the MV flow curves generated from velocity-encoded CMR acquisition [37]. In addition to stenotic valvular evaluation, MRI can also detect abnormalities in the subvalvular apparatus, associated left atrial or atrial appendage thrombi, and presence and severity of concomitant regurgitation.

Cardiac Computed Tomography CCT with electrocardiography (ECG)-gating with excellent spatial resolution allows visualization of the abnormalities involving the valves, cardiac chambers and great vessels. While transvalvular velocities and pressure gradients cannot be assessed by computed tomography (CT), the use of multi-phase data sets obtained during ECGgating facilitates a cine movie loop, thereby allowing for cusp excursion/apposition assessment [38]. Primary use of CCT for valve assessment should be considered carefully and weighed against the risk of radiation. CCT is probably the best imaging modality to quantitate the extent of calcification and therefore, the severity of MAC, which is not feasible by other imaging modalities (Figure 11.4A). In terms of dynamic functional assessment of native MV, it is best assessed at 5% and 65% of the RR

Multimodality Imaging in Cardiovascular Medicine

interval in the longitudinal axis [39]. The role of CCT in mitral stenosis is limited, but may offer auxiliary or initial information on presence of disease. Direct evidence of disease include leaflet or chordae thickening, calcification, and limited leaflet excursion in end-diastolic phase [38]. Planimetry of valve can be performed with good success [40]. Intimations of disease when direct assessment of the valve is not possible include extensive MV calcification, enlarged left atrium, or right-sided heart dilation along with pulmonary artery enlargement. CCT is unique in its reliable evaluation of functionality of the mechanical prosthetic valve mainly, in patients with bileaflet valves. Echocardiographic interrogation of mitral mechanical prosthesis can be challenging due to suboptimal visualization of valve motion and variation in transprosthetic Doppler-derived pressure gradients. CCT with its intrinsic multiplanar or 3D capabilities compared to fluoroscopy allows optimal visualization of the valvular motion independent of patient position, physical characteristics, limitation of C-arm motion, and operator skills (Figure 11.5) [41]. For a normally functioning bileaflet valve, the residual angle must be less than 20 degrees [42]. As a presurgical noninvasive imaging technique, CCT could be valuable in providing concomitant valvular and coronary assessment in patients with suspicion of mechanical valve dysfunction. Mitral Regurgitation Numerous pathologic processes by interfering with the Â�complex coordinated activity of the MV result in a common pathway—mitral regurgitation (MR). MR can be classified based on (a) chronicity of MR (acute or chronic),

F I G U R E 1 1 . 4 â•… (A) Mitral annular calcification on 2-dimensional (2D) transthoracic echocardiography (TTE) study. (B) Leaflet calcification as visual-

ized on a 3D volume-rendered image of the mitral valve (MV) on a transesophageal echocardiography study. (C) MV and left atrial calcification on a cardiac computed tomography study.

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F I G U R E 1 1 . 5 â•… Cardiac computed tomographic evaluation of a bileaflet prosthetic valve in the mitral position. (A) Three-dimensional (3D) volume-

rendered reformation of a normally functioning bileaflet valve. (B) 3D volume-rendered reformation displaying a thrombosed leaflet during diastole. Images courtesy of Dr. Joseph Lodato.

(b) the affected portion of the MV apparatus or ventricular wall (primary/organic or secondary/functional), and (c) mobility of the MV in respect to the MV annulus (Carpentier classification) [43]. Patients with acute MR will usually present with significant symptoms and a soft or absent holosystolic murmur. Acute MR due to papillary muscle rupture, chordal rupture, or leaflet disruption can occur from acute myocardial infarction, endocarditis, trauma, rheumatic disease, myxomatous degeneration, connective tissue disease, or infiltrative cardiomyopathy. The left ventricle is usually hyperdynamic and the left atrium is still normal in size in acute severe MR. These acute causes of MR are also potential contributors to chronic causes of MR. However, as opposed to the acute setting, the cardiac chambers have time to accommodate the gradual change in volume overload that occurs over a considerable period of time. Consequently, long-term accommodation or compliance to severe MR results in left ventricular and atrial enlargement, and possibly, pulmonary hypertension. When the MV apparatus is primarily involved, it is termed primary or organic MR. Degenerative MV disease, rheumatic heart disease, and endocarditis are the main causes of primary MR. Conversely, if changes in ventricular geometry are mechanistically responsible for MR, this is known as secondary MR, which commonly occurs from ischemic, infiltrative, or dilated cardiomyopathy. Myxomatous MV disease is the most common cause of MR in the developed world followed by ischemic heart disease (Table 11.2) [44,45]. In contrast, in the developing countries, the prevalence of myxomatous MV disease is unknown and the most common cause of MR appears to be rheumatic heart disease [46,47]. The mechanism of MR as classified by Carpentier is based on the motion of the MV leaflet in respect to the mitral annulus and is divided into three main types: (1) type I is defined as normal leaflet motion despite presence of pathology

(eg, dilated cardiomyopathy or perforated mitral leaflet due to endocarditis), (2) type II is defined by excessive leaflet motion typically seen in myxomatous degeneration or papillary muscle dysfunction or rupture from myocardial infarction, (3) type III is restricted leaflet motion which may occur in diastole (type IIIa) (eg, rheumatic disease) or during systole (type IIIb) (eg, coronary disease) [43].

Echocardiography A 2D Doppler echocardiography is helpful in not only determining the lesion and severity of MR but also defining the anatomic mechanisms responsible for the MR. Since echocardiographic MR evaluation includes left and right ventricular size and function, left atrial size, and pulmonary artery pressure measurements, it plays an integral role in determining the timing of MV repair or replacement. Hence, transthoracic echocardiography (TTE) is indicated for baseline evaluation of MR. It is used for surveillance in asymptomatic patients or those with changes in their symptoms. A systematic preoperative or intraoperative TEE study of the MV is paramount not only for confirmation or proper assessment of the mechanism of MR and the extent of the lesion involved, but also for making anatomic measurements, identification of concomitant valvulopathy other than MR requiring intervention, guiding surgical procedure to reduce incidence of postoperative systolic anterior motion, optimization of annuloplasty ring size, and evaluation of postsurgical paravalvular or intravalvular leaks. Transesophageal study is most widely used in patients who need further evaluation when the TTE study is inconclusive regarding MR severity, its mechanism, or left ventricular function [48]. In the midesophageal position, assessment of MV requires meticulous review from multiple angles. By maintaining the TEE probe in a good acoustic window at the level of the midesophagus, a 4-chamber view is usually obtained at 0 to 30 degrees demonstrating the A2–P2 scallops (Figure 11.1).

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F I G U R E 1 1 . 6 â•… Flail mitral valve. Two-Â�

dimensional (2D) transesophageal echocardiography (TEE) images reveal a P2 scallop flail mitral leaflet (A–C) with a corresponding 3D volumerendered TEE image from a left atrial orientation (D).

While maintaining the same angle, the probe can be further manipulated to allow visualization of other segments. Further increase in angle to about 60 to 70 degrees results in the bicommissural view allowing visualization of the P1–A2–P3 scallops. Rotating to 90 to 100 degrees, brings the P3–A3 scallops into view and rotating to an additional 120 to 130 degrees allows visualization of P2–A2 in the long-axis view. 2D images of these views are seen in Figure 11.1, with corresponding cut planes placed on a 3D image of the MV from the left atrial orientation. The diagnosis of MV prolapse and flail leaflets are well established with TEE, specifically, multiplane TEE with high sensitivity (78%–97%), specificity (92%–97%), and diagnostic accuracy (88%–97%) (Figure 11.6A–C) [49–51]. On 2DE, presence of structural abnormalities such as a flail leaflet or ruptured papillary muscle is pathognomonic for severe MR. Other signs of severity such as increased left atrial and ventricular size are less reliable and dependent on chronicity of MR. Indirect qualitative parameters used to determine MR severity include the regurgitant jet density and shape on continuous-wave Doppler spectral display, pulmonary vein systolic flow, MV inflow Â�velocity, and jet area using color Doppler, as shown in Figure 11.7. A dense and early peaking continuous-wave Doppler of the regurgitant jet, systolic flow reversal in the pulmonary vein, E wave dominance (E velocity .1.2 m/s) on mitral inflow, and a jet area of

.10 cm2 or .40% jet to left atrial area may signify severe MR. There are technical and hemodynamic limitations associated with these parameters, for instance, jet area may be underestimated in eccentric wall hugging jets. More quantitative parameters include vena contracta (VC), effective regurgitant orifice area (EROA), regurgitant volume (RV), and regurgitant fraction (RF) measurements (Figure 11.8). The grading of MR severity based on these parameters is documented in Table 11.3. VC width should be performed in a high-resolution, zoom mode in a longaxis window (Figure 11.8A). The width of the narrowest portion of the jet reflects the regurgitant orifice. The EROA and RV are calculated based on the presumption that flow convergence when approaching an orifice forms isovelocity shells, as seen in Figure 11.8B. A zoomed view of flow convergence, adjustment of the baseline shift toward the direction of flow or lowering of the Nyquist limit (which reduces the wall filter), radius measurement, angle correction, and continuous-wave MR Doppler are all performed to calculate EROA and RV. With all the variables involved in the flow convergence method, it is fraught with limitations that may underestimate or overestimate MR severity. Using this method for eccentric MR and multiple jets is also problematic. Preliminary studies using 3DE-derived anatomic regurgitant orifice area measurements indicate its use as adjunctive means of assessing MR severity in patients

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F I G U R E 1 1 . 7 â•… Qualitative assessment

of mitral regurgitation. (A) Mitral E velocity .1.2 cm/s. (B) Continuous-wave Doppler density and cutoff sign. (C) Pulmonary vein Doppler showing systolic flow reversal. (D) Color Doppler demonstrating regurgitant jet area in parasternal long-axis.

with eccentric or multiple MR jets. RF has been used as a reference standard in studies evaluating new quantitative methods for MR severity. This formula subtracts the stroke volume through the aortic from the MV, which is then subsequently divided by the MV stroke volume. This method is also problematic since there is an assumption that both LVOT and MV annulus are circular in addition to errors introduced by alignment of pulse Doppler sampling and modal velocity tracing. The role of 3DE in MR is evolving with further development in technology. Historically, 3DE has provided insight into the normal saddle shape of the MV annulus, which had implications on the diagnosis of MV prolapse [52]. Based on this finding, the diagnosis of MV prolapse is made in a long-axis view. Feasibility of 3DE evaluation of MV is highly dependent on image quality and therefore, when patients with good image quality were selected for a study, excellent visualization of the MV was achieved 98% of the time. Although transthoracic 3DE may allow identification of leaflet prolapse, 3D TEE has better resolution, hence, improved sensitivity, as seen in Figure 11.9 [53–56]. Posterior (P1, P3) and anterior leaflets abnormalities are better delineated by RT3D TEE compared to 2D TEE [55]. 3DE is also better at identifying ischemic MR by demonstrating the mechanisms responsible by projecting mitral annular and papillary muscle geometric alterations clearly along with segmental ventricular remodeling. Significant segmental left ventricular remodeling can cause posterior leaflet tethering and therefore, MR irrespective of left ventricular dilatation [57].

Using the fully sampled matrix array transesophageal probe, quick online 3D evaluation and quantitative analysis of the MV enables wider clinical application of this technology. The application of 3DE in evaluating regurgitant jets is currently focused on feasibility of 3D visualization of the regurgitant lesion, quantifying RV, measuring and noting the shape of the VC and PISA as shown in Figure 11.10A [58–61]. However, there are inherent limitations to the flow convergence methods, especially in patients with degenerative or primary MR and not to mention problems associated with acquisition of 3D color flow data. Direct measurement of the anatomic regurgitant orifice without the use of color Doppler methods may provide another solution for estimation of severity (Figure 11.10B). Lastly, with the emergence and increased interest in percutaneous reparative solutions to MR, the role of imaging in successful deployment of the device has become even more vital. O’Gara et al have outlined 4 fundamental imaging objectives: (1) evaluate the mechanism and severity of MR, (2) determine anatomic suitability for device repair, (3) guide deployment of the device, and (4) assess stability and outcome of repair [62]. Transesophageal imaging with 3D capability is most suitable for meeting the objectives outlined above.

Cardiac Magnetic Resonance Imaging A complete MR evaluation by CMR involves both morphologic and volumetric assessment. Morphologic assessment consists of initial views of the MV in the 2, 3, and 4-chamber

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F I G U R E 1 1 . 8 â•… Quantification of mitral regurgitation. A, Vena contracta. B, Effective regurgitation orifice area (EROA) and regurgitant volume (RV)

calculation.

F I G U R E 1 1 . 9 â•… Degenerative mitral valve disease. Three-dimensional (3D) transesophageal echocardiography using zoom mode allows better visu-

alization of mitral valve anatomy usually displayed from a left atrial perspective. (A) Multisegmental prolapse involving P1–P3 with a flail P1 Â�segment. (B) Example of a patient with flail P2 segment. (C) Example of a patient with multisegmental, bileaflet degeneration with severe prolapse of P2 and flail P3 segment.

jâ•… Table 11.3â•… Etiologies of chronic mitral regurgitation • Primary mitral regurgitation • Degenerative or myxomatous: Barlow’s disease, Fibroelastic deficiency, Marfan’s syndrome • Rheumatic heart disease • Hypertrophic obstructive cardiomyopathy • Connective tissue disease: rheumatoid arthritis, systemic lupus erythematosus • Endocarditis: healed or acute • Others: radiation, pharmacologic agents, mitral annular calcification,congenital • Secondary mitral regurgitation • Ischemic mitral regurgitation • Dilated cardiomyopathy

long-axis views and if necessary, further segmentation from a basal short-axis slice [63]. From the chosen short-axis slice, a contiguous stack of oblique slices are aligned orthogonal to

the central part of the line of coaptation, oriented approximately parallel to the 3-chamber LVOT long-axis plane. The stack of cines are acquired starting from the superior (anterolateral) commissure adjacent to A1–P1 and the inferior (posteromedial) commissure adjacent to A3–P3 using a slice thickness of 5 mm and with no interslice gap. Typically, 2–3 slices pass through each of the valve scallops (A1–P1, A2–P2, and A3–P3). Orthogonal orientation of the slice relative to a thin structure or boundary depicts the structure more clearly than oblique orientation [63]. From this, each component of the MV (A1–A3, P1–P3) is identified and any associated dysfunction is defined, but CMR is limited in its ability to provide mechanistic insight as adequate visualization of the chordal structures identifying rupture or elongation is not currently feasible. However, emerging and published data support improved ability of CMR to morphologically delineate and guide surgical intervention accordingly in degenerative MV disease (Barlow’s or fibroelastic deficiency) [64,65].

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F I G U R E 1 1 . 1 0 â•… Three-dimensional (3D) color Doppler and anatomic regurgitant orifice area (AROA) on a 3D rendered surface obtained with

software designed for quantitative analysis of the mitral apparatus. (A) 3D color Doppler of a mitral valve (MV) shown in multiplanar reconstruction views. Two orthogonal views with a short axis through the vena contracta (upper and lower left panels). The left atrial perspective of MV shows a flail P2 scallop during 3D transesophageal echocardiography (right lower panel). (B) Postacquisition analysis of MV demonstrates the complex, 3D AROA in color-coded 3D rendered surface representing a topographical map of the mitral apparatus.

Quantification of MR is not only feasible by CMR, it can but also concomitantly provide pertinent and accurate assessment of the MR’s effect on ventricular volume, mass, and function [66–68]. This can be very useful when timing surgical intervention in equivocal cases. Qualitative visual assessment of MR severity as judged by presence of signal void on MRI, which while corroborating the quantitative findings, is not reliable as a sole measure of severity. Quantitative parameters such as regurgitant volume (RV) and fraction either calculated by velocity-encoded (MR) imaging or indirectly via volumetric analysis have correlated well with measurements obtained from cardiac catheterization and 2DE. RV is calculated by determining the difference between left ventricular (LV) and the aortic forward flow stroke volume (MRV [mL] 5 LVSV – AoSV). RF is determined by dividing the mitral RV by the LV stroke volume (RF (%) 5 (MRV 4 LVSV) 3 100). This is feasible even with concomitant aortic regurgitation as long as the aortic systolic flow is measured accurately. In setting of isolated MR, difference in RV and LV stroke volumes can be used to quantitate mitral RV (MRV 5 LVSV – RVSV). Alternatively, direct measurement of the RV can be achieved by measuring forward and backward flow at the level of the MV by applying phase-contrast velocity encoding at the tips of the MV leaflets perpendicular to the direction of the MV inflow at end-systole. Velocity-encoded MR (VENC) imaging can be challenging due to cardiac motion, which can be theoretically overcome with through-plane motion correction by

taking into account myocardial velocity and subtracting it from the through-plane MV flow velocities [69]. In comparison to 2D one-directional VE MR imaging, 3D 3-directional MR imaging (VE in 3 orthogonal directions) has shown Â�better correlation with aortic systolic stroke volume measurements and additionally, has avoided overestimation of MR as observed with 2D VE-MR technique [70]. CMR provides an opportunity to directly visualize the regurgitant orifice and therefore, allows measurement of the anatomic regurgitant orifice area. Planimetry of CMR regurgitant orifice area using SSFP sequences has been shown to correlate well with echocardiographic and cardiac catheterization measures of MR; however, its limitations include potentially an underestimation or overestimation of the orifice area due to imprecise localization and valve motion [71]. Extensive calcification of the mitral annulus may present a formidable surgical challenge during MV surgery with ensuing complications that include paravalvular leaks, dehiscence, ventricular rupture, and atrioventricular disruption. Unfortunately, CMR is limited in its ability to quantitate the full extent of annular calcification. CMR’s strength may lie in its utilization of late gadolinium enhancement to detect scar burden in ischemic MR patients; differentiate those who are most likely to Â�succeed from MV intervention. Moreover, in patients with ischemic MR, regional LV viability and contractile reserve can be further assessed by utilizing low-dose dobutamine

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annular structure; detailed 3D analysis has demonstrated that this clinically defined region is not circular, but frequently elliptical [77–79]. The base of each leaflet adheres to the aortic root in a semilunar configuration, with the inferior aspect of the leaflet base attached to the ventriculoarterial junction of the aortic root, and the supeCardiac Computed Tomography rior aspect of the leaflet base attached to the sinotubular In MR, determinants of surgical timing include LV function;Â� junction. The left and right coronary arteries usually are 64–multidetector computed tomography (MDCT) assess- located at or below the level of the sinotubular junction. ment of LV global function has been demonstrated to The aortic root complex appears simple but is complex in be accurate and reliable compared to cardiac MRI [72]. its relationship anatomically and mechanically with other Quantitative assessment of RV by CT in setting of iso- valves, such as the MV and the left ventricle. The leaflets lated MR is feasible by measuring the stroke volumes of arise from ventricular muscle only over part of their cirthe left and right ventricles which has shown respectable cumference. The larger part of the noncoronary leaflet of concordance to CMR measurements [73]. Planimetry the valve, along with part of the left coronary leaflet, is in of mitral regurgitant orifice area is feasible and has cor- fibrous continuity with the aortic or anterior leaflet of the related well with semiquantitative analysis performed by MV [80]. ventriculography or TEE [74]. However, application of this Imaging the aortic valve usually encompasses all of technique is limited as it necessitates retrospective gating the components of the aortic root complex. Measurements with inability to dose modulate and consequently requires of the aortic root include the aortic valve annulus, the higher radiation doses. Contrast-enhanced CT in ischemic maximum diameter of the sinuses of Valsalva, sinotuMR may reveal coronary artery calcifications or plaque. bular junction, and the tubular portion of the ascending There is an emerging role of CT in preplanning for per- aorta [81]. CT, 3DE, and MRI, are emerging as attractive cutaneous mitral annuloplasty—a semi-invasive reparative modalities especially in patients with connective tissue solution to MR. Crucial to the success of this procedure is disorders or bicuspid aortic valves because they permit identification and location not only of the variable coro- precise measurement of the aortic root at any desired level nary venous anatomy but also of coronary arterial anat- or plane. Thus, they may provide more accurate measureomy in order to avoid its extrinsic compression [75,76]. ments of the true dimensions of the different components The use of CCT allows simultaneous visualization of of the aortic valvular complex. Imaging also plays an intevenous, coronary artery, and cardiac anatomy as well as gral role in surgical and percutaneous interventions in the postdeployment assessment of device position and mitral aortic position as accurate sizing becomes increasingly annular remodeling; all of which are imperative to proce- critical. dural successÂ�[62]. MDCT offers the advantage of better visualization and measurement of the opening angle of the prosthetic Aortic Stenosis valve relative to the annular plane in multiple planes, and Aortic valve stenosis of nonrheumatic or congenital origin while it can identify obstruction of the valve, it cannot is the most common valvular heart disease in the western differentiate fully between pannus and thrombus. This world and increases in prevalence with each decade of life ability to visualize leaflet motion, specifically in bileaf- [82–84]. Conversely, rheumatic aortic stenosis (AS) is more let valves (more challenging in single leaflet, translucent prevalent worldwide. Stenosis in rheumatic AV disease valves), can play a complementary role in dispelling spu- results from commissural fusion, aortic cusp thickening, and rious cases of prosthetic valve stenosis related to pressure calcification. AS is a disease spectrum spanning from nonrecovery, thereby, avoiding invasive studies such as TEE calcified to calcified etiologies (Table 11.4). Calcific aortic or catheterization. valve disease itself is a continuum from mildly thickened, stress at 5 and 10 mcg/kg/min followed by gadolinium. CMR is able to provide a detailed and comprehensive assessment of the MV leaflets and dysfunction, and LV size, function, and viability in a single examination.

jâ•… AORTIC VALVE The aortic valve is part of the aortic root complex, which spans from the basal attachments of the valve leaflets to the sinotubular junction. A normal aortic valve consists of 3 leaflets with the left coronary, right coronary, and noncoronary leaflets attaching just below its own sinus of Valsalva thereby, creating a vortex for valve closure. The aortic valve does not have a truly circular or discrete

jâ•… Table 11.4â•… Mitral regurgitation severity Quantitative

Mild

Effective regurgitant orifice area (mm2)

20

Moderate 20–39

Severe 40

Regurgitant volume (mL/beat)

,30

30–59

.60

Vena contracta (cm)

,0.3

0.3–0.69

.0.7

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F I G U R E 1 1 . 1 1 â•… Continuity equation for the calculation of aortic valve area.

nonobstructive, mildly calcified cusps to severely calcified disease with limited leaflet excursion which in its severe form prognosticates poor survival [85,86]. Bicuspid aortic valve (BAV) disease and Marfan syndrome, congenital causes of AS, have coexisting aortopathy, which can manifest as aortic dilation, dissection, or rupture, and may occur irrespective of presence of valvular hemodynamic abnormalities [84,87–92]. In AS, progressive valvular obstruction gradually results in an increase in afterload with ensuing concentric left ventricular hypertrophy, diastolic dysfunction, and pulmonary hypertension. Although there is also an increase in coronary flow, it is inadequate to accommodate the increase in left ventricular muscle mass and thereby, contributes to the patient’s symptomatology. Consequently, assessment of aortic valvular pathology demands a comprehensive evaluation including morphology, extent of calcification, leaflet excursion, and hemodynamics, as well as concomitant assessment of LV geometry and function, presence of coexisting cardiovascular diseases including aortic root disease, and coronary artery disease.

Echocardiography Echocardiography is indispensable in its role in making the diagnosis of AS. The severity of AS is based on jet velocity, mean transaortic gradient, and valve area calculation from continuity equation, as shown in Figure 11.11 and

Table 11.5 [93]. The degree of stenosis assessment by the continuity equation is well validated, less flow dependent, and is based on the principle that stroke volume is equal on either side of the orifice [94,95]. Unfortunately, it is subject to errors in LVOT diameter measurement. Accurate calculation of the AV area relies on the dynamic flow parameters across the valve, which involves measuring the maximal velocity and mean gradient from multiple acoustic windows in search of the highest signal. The peak velocity and its rate of increase over time is a strong predictor of clinical outcomes in patients with AS [86,96,97]. However, underestimation of AS severity with velocity and gradient measurements can occur when the forward stroke volume is low. Other means of assessing severity, include transthoracic 2D echocardiographic planimetry of the stellate-shaped jâ•… Table 11.5â•… Etiologies of aortic stenosis • Congenital abnormality (unicuspid or bicuspid) • Calcific disease (degenerative, chronic kidney disease) • Rheumatic valve disease • Rare causes: • Metabolic disease (ie, Fabry’s disease) • SLE • Paget disease • Alkaptonuria

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F I G U R E 1 1 . 1 2 â•… Echocardiographic evaluation of calcific degenera-

tive and bicuspid aortic valve. (A) Two-dimensonal (2D) transesophageal echocardiography (TEE) image of a calcific degenerative aortic valve. (B) 3D echocardiogrpahic volume-rendered image of calcific aortic stenosis. (C) A 2D TEE image of a bicuspid aortic valve in systole demonstrates a football-shaped orifice and raphe (white arrow). (D) 3D volume-rendered image of a true bicuspid aortic valve during systole.

systolic orifice in AS. It has been demonstrated to be feasible and reliable when compared to the continuity method, planimetry by TEE, and cardiac catheterization. However, heavily calcified valves, commissural fusion, tangential imaging plane, and echo drop pose limitations to this technique (Figure 11.12) [98]. Of note, area measurement from planimetry by echocardiography or any other imaging modality is not necessarily equivalent to effective orifice area obtained by continuity or Doppler method, which represents the minimal cross-section of the flow jet downstream from the stenotic aortic valve and has been validated as a predictor of outcome [99]. Comparison of effective orifice area obtained from echocardiography to the anatomical orifice measured by 3DE, TEE, CT, or MRI is not straightforward since orifice rigidity or deformation, calcification, and flow rate can affect the contraction coefficient [100]. A reliable alternative for evaluation of severity is the dimensionless index, which is the time velocity integral ratio of VTILVOT/VTIAorta. This formula eludes the errors related to LVOT measurements and corresponds to the severity of the AV area with a VTI ratio of less than 0.25 signifying severe stenosis [94]. Potential limitations to overcome while determining stenosis severity by echocardiography, include low cardiac output, concomitant aortic or mitral regurgitation, severe valvular calcification, poor acoustic windows, and improper gain settings [94,98,101,102]. Combination of these conditions can result in inaccurate measurements of the LVOT and improper Doppler alignment, recording of MR jet instead of aortic inflow, therefore, resulting

Multimodality Imaging in Cardiovascular Medicine

in under- or overestimation of valve area. Since LVOT is squared in the continuity equation, it has the potential to be a source of considerable error when determining the transvalvular gradient. Echocardiography with dobutamine infusion is a solution to the pitfall associated with the low cardiac output state. In the setting of low-flow, low-gradient AS, dobutamine echocardiography not only identifies true fixed stenosis but also prognosticates postsurgical success in those with poor contractile reserve [103–105]. Echocardiographic studies for AS are incomplete without ascertaining the effects and comorbidities associated with the stenotic lesion. These coexisting or resultant abnormalities include left ventricular hypertrophy, diastolic dysfunction, regional and global systolic function, aortic dilation, MV disease, left atrial dilation, and pulmonary hypertension. TTE serves as an ideal serial imaging modality in this disease process; the appropriate surveillance intervals are guided by clinical recommendations based on disease severity and comorbidities [48]. When TTE studies are limited by poor acoustic windows, TEE may be used for further diagnostic assessment of the severity of AS. TEE determination of valve area is planimetric in its approach, but is not feasible when the valve is heavily calcified [70,106]. It does facilitate unhampered measurement of the aortic root when TTE acoustic windows are suboptimal (Figure 11.13). Even though transvalvular gradients can be attained from the transgastric 5-chamber views, they are usually less reliable due to inability to attain a parallel intercept angle between the jet and the continuous-Â� wave Doppler. TEE is necessary intraoperatively to determine prosthetic valve sizing and seating, valve function postoperatively, and to detect valvular or paravalvular leaks after valve replacement or valve-sparing repairs in the aortic position. With its high negative predictive values, TEE’s higher resolution images are essential in ruling out aortic valve involvement from vegetation, abscess, thrombus, and fistula formation in a clinically indicated situation [107]. Percutaneous aortic valve implantation is an emerging alternative for patients deemed unsuitable for surgery with severe AS. There is an evolving integrated approach using ultrasound technology comprising of 2D transthoracic, transesophageal, intracardiac, and/or 3D imaging during the percutaneous aortic valve implantations. From procedural preplanning utilizing TTE for measurement of annulus, LVOT, and aortic dimensions guiding appropriate prosthesis size and selection to use of TEE for aortic atheroma detection, deployment and placement of valve, and postdeployment paravalvular leak assessment, echocardiography is integral to aortic valve implantation [108]. BAV is the most common congenital heart defect occurring in 1% to 2% of the general population [109–112]. The clinical relevance of this anomaly is important due to associated valvular pathology and aortopathy which has a propensity for dissection posing serious morbidity and mortality to this BAV patient population [89,91,113]. Identification of a

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F I G U R E 1 1 . 1 3 â•… Two-dimensional biplane transesophageal echocardiography image of the aortic valve. (A) Cross-section of the aortic valve. (B) Parasternal long-axis view of the aortic annulus and root. Dimensions: (a) annular, (b) sinuses of valsalva, (c) sinotubular junction, (d) proximal aorta (approximately 4 cm from the annulus).

BAV with and without stenosis or regurgitation is easily performed by TTE or TEE (Figure 11.12C and D). Even in normally functioning BAV, aortopathy develops independent of valvulopathy [114–116]. Hence, complete evaluation of the thoracic aorta is paramount but may not be feasible with echocardiography, therefore, CMR and CCT are becoming useful complementary imaging modalities as both, initial and surveillance studies (Figures 11.14 and 11.15).

Cardiac Magnetic Resonance Imaging Magnetic resonance imaging allows anatomic and functional assessment of the aortic valve and aortic root (Figure 11.14A). SSFP and gradient-echo cine pulse sequences can visualize flow turbulence (Figure 11.14B) on the basis of loss of signal (signal void) due to the dephasing of moving protons, and can therefore, show the presence, location, possible severity and optimal location for velocity sampling. Quantitative analysis of the aortic valve area by CMR can be performed in 2 different ways: anatomic valve area and physiological valve area. CMR planimetry of the aortic valve is a reliable technique and correlates well with echocardiographic parameters [117]. Cardiac MR planimetry has demonstrated acceptable sensitivity and specificity for the detection of severe AS versus other noninvasive techniques and cardiac catheterization [117]. Both planimetry and continuity equation-based measurements of AVA by CMR, when compared to TEE, have demonstrated high correlation, however, as expected, CMR AVA has been observed to be larger by planimetry than by continuity equation [118]. This is

consistent with previous findings that maximum anatomic opening of a stenotic aortic valve appears to be larger than the size of the functional VC [119]. Preliminary studies in patients with bioprosthesis in aortic position have shown CMR planimetry of the orifice area to be feasible and consistent with echocardiographic measurements derived from continuity equation, thus making it an alternative approach in those with poor acoustic windows. AS evaluation by CMR allows for a comprehensive study, including ventricular function, the extent and pattern of left ventricular hypertrophy, presence of subaortic membranes; all of which play a role in determining the timing or need for surgery. Limits to MRI evaluation of aortic valve area include difficulties in edge Â�discrimination due to the signal void caused by highly calcified valves. In bicuspid patients, CMR’s utilization of planimetry, excellent visualization of the aortic valve, velocity-encoded imaging, and magnetic resonance angiography, make it an ideal surveillance modality for both progression of aortopathy and valvulopathy. Cine CMR of the aortic valve can be 100% sensitive and 95% specific in distinguishing bicuspid from normal aortic valves (Figure 11.14A and C) [120]. Although CMR allows anatomic and functional assessment of the AV and root, it is not as useful as CT for preprocedural planning for percutaneous AVR since the plane of imaging has to be chosen at the time of the examination and cannot be changed by subsequent manipulation of the data set. Additionally, signal void caused by calcium and metal preclude precise assessment of densely calcified valves and the stent/valve after transcutaneous AV implantation. Even though clinically acceptable degree of agreement has been demonstrated between measurements of peak jet

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is not perpendicular to the valve plane, an under-sampling of the peak velocity can occur. Preliminary acquisition of an in-plane–encoded velocity map can help. Identification of the direction of flow and the velocityencoding range are needed. A more robust method to measure the velocity would be to acquire a complete 3D velocity-encoding data, but it may result in an increase in imaging time. Measurement of ventricular volume by CMR has been proven to be independent of geometric assumptions, and more accurate, and reproducible. Combining measurements of stroke volume by CMR with measurements of VTI across the AV by echocardiography in a hybrid approach takes advantage of the excellent accuracy and reproducibility of CMR while avoiding the problems associated with echocardiographic determination of LVOT diameter and LVOT flow [124]. However, this approach is time consuming; requires multimodality imaging; excludes patients with atrial fibrillation, severe MR, and left-to-right shunts; and has not been validated in the low-gradient AS patient.

Cardiac Computed Tomography

F I G U R E 1 1 . 1 4 â•… (A) Cardiac magnetic resonance image (MRI) of a normal aortic valve in short-axis (A) and in a patient with a bicuspid aortic valve (BAV) and aortopathy (B–E). (B) Cine steady-state free-precession image in a coronal oblique view demonstrating the flow turbulence across the BAV. (C) Cross-sectional view showing the BAV with calcified leaflets. (D) Phase-contrast imaging of the BAV demonstrating appropriate encoding velocity in the phase image. (E) Phase image of the BAV demonstrating aliasing resulting from setting the encoding velocity lower than the true peak velocity within the region of interest.

velocity by MR velocity–encoded phase-contrast imaging and by Doppler echocardiography, CMR has been shown to mildly underestimate both peak velocity and VTI compared to echocardiography [121.122]. Divergence between CMR and echocardiographic data is especially noted beyond the threshold for defining critical stenosis. This point is reached when the aortic VTI is 4 times that of LVOT with preserved LV function [123]. Difficulties with MR phase-contrast estimation of velocity in AS include effects of turbulent flow, intravoxel dephasing signal loss in high-velocity jet, aliasing (Figure 11.14D and E), partial volume averaging, long acquisition times, inability to accommodate arrhythmia, balancing act of spatial and temporal resolution, and meticulous alignment of the correct plane for maximum velocity measurement. If the flow

MDCT assessment of aortic valve, unlike echocardiography and MRI, is entirely anatomic (Figure 11.15). Planimetric measurements of aortic valve area on CT are similar to those achieved by echocardiographic measurements, but larger compared to the area calculated with the continuity equation (Figure 11.15D) [88,125,126]. This discrepancy between the two measured values is partially due to differences in LVOT area based on LVOT diameter versus direct planimetry of the LVOT area and likely, due to the coefficient contraction [109,127,128]. Computed tomographic evaluation of aortic annual diameters in multiple views has demonstrated an elliptical rather than circular geometry [79]. Due to higher temporal and spatial resolution compared to MRI, in patients with poor acoustic windows, CT offers a confident evaluation of leaflet morphology, thickness, and calcification. This is especially useful in bicuspid aortic valve patients requiring a simultaneous evaluation of the aorta (Figure 11.15A and C). CT is unparalleled in its ability to quantify coronary calcification and offers analogous quantitation of valvular calcification (Figure 11.15E). Aortic valve Agatston calcium scores correlate with severity of stenosis and predict event-free survival in asymptomatic patients with AS; however, there is variability in these scores depending on the timing of image reconstruction [129–131]. While CT is not an appropriate initial diagnostic study in patients with AS, it can serve a multipurpose role in those being considered for surgery. CT can confirm the severity of stenosis, evaluate coronaries for potential bypass grafting, assess aortic size, presence of calcification as well as biventricular size and function. CCT with its fast acquisition of volumetric data sets and subsequent 3D display and reconstruction capability in unlimited planes, especially of the aortic root, is emerging in its role for presurgical planning for valve replacement, including transcatheter aortic valve replacement [132,133]. Limiting the

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F I G U R E 1 1 . 1 5 â•… Aortic valve imaging with cardiac computed tomography. (A) Volume-rendered image of a trileaflet aortic valve in cross-section. (B) Volume-rendered image of a bicuspid aortic valve (BAV) in cross-section (white arrrow). (C) Sagittal oblique volume-rendered image of aorta demonstrating proximal thoracic ascending aortic aneurysm and coarctation distal to the subclavian artery in the descending aorta in the patient with BAV. (D) Planimetry of aortic valve. (E) Sagittal reconstructed views of aortic root showing extensive calcification involving the aorta with mild involvement of the aortic valve. Courtesy of Dr. Joseph Lodato.

coverage during CT acquisition craniocaudally at the aortic root along with dose modulation, can significantly reduce the radiation exposure for this purpose. Annular and LVOT measurements performed easily on CT can be problematic by echocardiography not only due to poor acoustic windows but also there is an underestimation of LVOT and annular dimensions by both 2D and 3D TEE in comparison to multislice computed tomography (MSCT) [134]. Additionally, by incorporating anatomic measurements from CT and velocity measurements from echocardiography into continuity equation, aortic valve areas can be generated by utilizing a multimodality integrated data set.

Multiplanar reformation at 5% to 10% of the R-R intervals facilitates dynamic aortic valve imaging throughout the cardiac cycle and a correct estimation of leaflet excursion. CT has significant advantages when it comes to evaluation of mechanical leaflet motion, analogous and even potentially superior to cine-fluoroscopy as the latter is subject to patient positioning (Figure 11.16) [41,135]. Prosthetic valve obstruction can be a serious and lifethreatening condition. Echocardiography offers suboptimal visualization of mechanical valve motion due to shadowing and reverberations from the valve. It is limited by the variation among transprosthetic Doppler-derived pressure

F I G U R E 1 1 . 1 6 â•… Cardiac computed tomographic evaluation of prosthetic valve in the aortic position with elevated transaortic gradient. (A) Three-dimensional volume-rendered maximum intensity projection (MIP) of a Bjork-Shiley valve. (B) Restricted opening of the tilting disc as demonstrated using multiplanar reformation (MIP) visualized in an oblique coronal view.

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174

gradients [136]. In cases of congenital aorta or bileaflet prosthesis in aortic position, pressure recovery can pose a challenge and give spuriously high transvalvular gradients. High velocities across the AV may also be secondary to intrinsic prosthetic obstruction or high flow. Alternatively, combination of prosthesis dysfunction and low cardiac output state may not generate high gradients. MDCT offers the advantage of better visualization and measurement of the opening angle of the prosthetic valve relative to the annular plane in multiple planes, and while it can identify obstruction of the valve, it cannot differentiate between pannus versus thrombus [137,138]. This ability to visualize leaflet motion, specifically in bileaflet valves (more challenging in single leaflet, translucent valves), can play a complementary role in dispelling spurious cases of prosthetic valve stenosis related to pressure recovery, thereby, avoiding invasive Â�studies such as TEE or catheterization. Limits to CT evaluation of aortic valve include exclusion of patients based on atrial fibrillation, contraindications to contrast as enhanced studies offer better morphological delineation of structure, and reluctance to expose patients unnecessarily to radiation. Valve planimetry or leaflet motion assessment necessitating a retrospective study without ECG dose modulation results in an average radiation exposure of 11 msV in a MSCT scanner, which is comparable to a Â�myocardial SPECT scan [139]. Interestingly, in asymptomatic AS, prospective studies have suggested that sudden death may be uncommon in the absence of preceding symptoms and imaging parameters; while they do establish the severity of disease, do not distinguish between those with and without symptoms nor do they mark a threshold for surgery [140]. Conversely, we are also presented with data demonstrating correlation of rapid progression (ascertained via imaging) with poor outcome in a subset of patients with asymptomatic AS [96]. As imaging becomes more integrated, hopefully it will play an even greater role beyond diagnostics to prognosis in this subset of asymptomatic patients. Aortic Regurgitation Aortic regurgitation (AR) results from the disruption of the aortic root complex consisting of the aortic leaflets, annulus, and the root; malfunction can involve any one or all of its components. The most common etiologies for AR include senile, calcific degenerative disease of the aortic valve, infective endocarditis, congenital bicuspid aortic valve, rheumatic heart disease, aortic dissection, systemic hypertension, use of anorectic drugs, and connective tissue disease (Table 11.6) [141–147]. Mechanistically, either it is leaflet or aortic root pathology that results in AR [148]. Leaflet lesions usually entail perforation from endocarditis or trauma, prolapse, retraction secondary to inflammatory or senile degenerative calcific process, or jet lesion from a subaortic membrane [148]. The aortic root pathology Â�contributing to

jâ•… Table 11.6â•… Aortic stenosis severity Quantitative

Mild

Moderate

Severe

AVA (cm )

,1.0

1.0–1.5

1.5

Mean gradient (mm Hg)

,25

25–40

.40

Peak velocity (m/s)

,3

3–4

.4

2

AR includes degenerative aortic dilatation, cystic medial necrosis, Â�connective tissue disease, hypertension, or aortopathy associated with bicuspid valve, Marfan syndrome, or conotruncal defects like Tetralogy of Fallot and truncus arteriosus. AR from aortic root dissection results from either disruption of the annulus or prolapse of the intimal flap into the intrinsically normal leaflets. Regardless of its etiology, AR leads to left ventricular pressure and volume overload with an eventual decline in systolic function. However, the consequence of an initially successful LV compensation, to an increased after and preload state, is a latent increase in wall stress [149]. The adaptive response of LV in chronic AR to increase in LV end-diastolic volume and pressure fails to occur in the setting of acute AR. As the high volume of regurgitation gets ejected into a high-pressure chamber, it overwhelms the LV with consequent hemodynamic deterioration. The etiologies responsible for acute aortic regurgitation are limited and include infective endocarditis, aortic dissection, sinus of Valsalva rupture, acute dysfunction of a prosthetic valve, and aortic balloon valvuloplasty.

Echocardiography Echocardiography is the most important diagnostic tool for diagnosis and grading of AR severity. It provides information on the presence and degree of AR, anatomy of the aortic leaflets, the root, and LV size and function [150]. The American Society of Echocardiography guidelines for quantification of valvular regurgitation emphasize integration of all pertinent information to properly evaluate patients with AR [151]. Simple indirect or supportive signs of severe AR on M-mode and 2DE include increase in ventricular dimension and E point to septal separation, fluttering or early closure, reverse doming, and increased echogenicity of the anterior MV leaflet [152,153]. Classifying the severity of regurgitation, which has important surgical implication, is the first step in Â�evaluating patients with aortic regurgitation (Tables 11.7 and 11.8). Aortic regurgitation severity is assessed using color and continuous-wave Doppler echocardiography. Color Doppler evaluation involves assessment of 3 difÂ� ferent components of the regurgitant jet: proximal flow convergence, VC, and the regurgitant jet below the level of the aortic valve within the LVOT (Figure 11.17). The regurgitant jet accelerates as it approaches the orifice forming a proximal flow convergence zone consisting of a series of shells with decreasing surface area and increasing velocities,

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jâ•… Table 11.7â•… Etiologies of aortic regurgitation

jâ•… Table 11.8â•… Aortic regurgitation severity

• Valve Leaflets: • Congenital abnormality (bicuspid) • Infective endocarditis • Rheumatic valve disease • Nonvalvular disease • Hypertension • Marfan syndrome • Connective tissue disease

Quantitative

Mild

Regurgitant volume (cc)

,30

20–44

45–59

60

Regurgitant fraction (%)

,30

30–39

40–49

.50

Effective regurgitant orifice area (cm2)

,0.1

0.1–0.19 0.2–0.29

with the flow rate at each isovelocity surface equaling that at the regurgitant orifice. The EROA, a quantitative measure of severity, is obtained by dividing the flow rate of the hemispheric velocity by the regurgitant peak velocity obtained from the continuous-wave Doppler. It is less reliable in the setting of aortic root dilation or eccentric jet [154]. The RV is derived as a product of the EROA and VTI of the AR jet. A RV 60 cc, an EROA 0.3 cm2, and a RF of 50% indicate severe AR. Just proximal to the orifice, the jet narrows into a high-velocity zone known as the VC before it exits into the LVOT. The measurement is taken at the smallest diameter just distal to the flow convergence region in the parasternal long-axis in a zoomed view and is considered a surrogate measurement for the size of the

Moderate

Severe

.0.3

orifice. Clinical studies have confirmed the usefulness of this measurement for judging AR severity. A VC diameter .0.5 cm is highly sensitive, while a diameter .0.7 cm is highly specific in making the diagnosis of severe regurgitation [155]. In AR, VC can be measured in a parasternal long-axis or short-axis view in a color Doppler mode. Conversely, a VC width ,0.3 cm is specific for mild AR [156]. The relationship of the jet to the LVOT can provide a clue to its mechanism. Eccentric jets are associated with bicuspid aortic valves or prolapse. Regurgitant jet width relative to the LVOT diameter is visualized on color flow imaging [157]. Further quantitation usually includes jet width/ LVOT width, and jet CSA/LVOT CSA (CSA, cross-sectional area) obtained in a parasternal long-axis and short-axis

F I G U R E 1 1 . 1 7 â•… Echocardiographic assessment

of aortic regurgitation (AR). (A) Two-dimensional (2D) color Doppler in a zoomed parasternal longaxis view of left ventricular outflow tract (LVOT). (B) Color M-mode at the LVOT demonstrating the height of the AR jet compared to the height of the LVOT. (C) 2D color Doppler in a zoomed parasternal short-axis view of jet of AR. (D) Flow convergence obtained from a zoomed apical 5-chamber view. (E) Continuous-wave Doppler spectral display of the regurgitant signal. (F) Holodiastolic flow reversal in the descending aorta using pulse-wave Doppler (white arrow).

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window, respectively (Figure 11.17B and C). The measurements should be performed immediately distal and within 1 cm of the valve. Ratios of 65% for jet width and 60% for jet area signify severe AR. RV and function can be calculated utilizing the continuity equation. RV is derived from the difference between the transaortic volume (SVTotal 5 CSALVOT 3 VTILVOT) and transmitral volume (SVMVinflow5 CSAMV 3 VTIMV). If concomitant MR is present, the stroke volume through the pulmonary artery would be an alternative for forward flow, whereas an alternative for total stroke volume could also be obtained by the difference between LV end-systolic and LV end-diastolic volumes. RF is obtained by dividing the RV from the LVOT stroke volume ((Aortic RV 4 LVOT SV) 3 100%). Qualitative parameters assessing AR severity include the PHT and reversal of flow in the aorta. Continuous-wave Doppler-derived regurgitation flow velocity of the AR jet is a reflection of the diastolic pressure gradient between the aorta and the LV (Figure 11.17E). The rate of deceleration and the derived PHT correspond to the rate of equalization of these pressures [158]. PHT is the amount of time required for the peak diastolic pressure gradient to fall by half, and a value less than 200 milliseconds typically indicates hemodynamically significant regurgitation. PHT is dependent on the LV compliance, systemic vascular resistance, loading conditions, and other associated valvular lesions. When the AR is severe, there is a more rapid dissipation of the gradient due to an increase in the LV enddiastolic pressure (LVEDP) resulting in a shorter half-time index [159]. This method may overestimate the degree of regurgitation in patients with high LVEDP from causes other than AR [158]. Evaluation of the flow pattern in the proximal descending aorta using PW-Doppler in the setting of severe regurgitation should reveal holodiastolic flow reversal, while no or only brief diastolic flow reversal indicates mild AR (Figure 11.17F). Even though these parameters are limited by instrument settings, loading conditions, Doppler alignment, regurgitant orifice shape, and eccentricity of the jets, in combination, they provide a congruent impression of severity [160]. Grading the severity of AR should not be based on a single parameter or several qualitative signs, but a comprehensive view of all indirect signs and qualitative and quantitative measurements using Doppler echocardiography. For instance, if there is a small jet width, with a faint Doppler profile, and a deceleration rate of .500 milliseconds, then it is consistent with mild AR. However, a wide jet/LVOT ratio, a dense Doppler spectral profile similar to aortic outflow, a steep deceleration rate of ,200 milliseconds, and presence of holodiastolic reversal of flow in the descending aorta combined indicate severe AR. The indications for surgery are clear in symptomatic patients with severe AR. In those without symptoms, based on post-AV replacement clinical outcomes and LV function, surgical intervention is recommended when EF falls below 50% or when there is severe LV dilation, defined as an end-diastolic

Multimodality Imaging in Cardiovascular Medicine

dimension more than 75 mm or an end-systolic dimension more than 55 mm [161,162]. However, absolute LV diameter (ie, uncorrected for body size) tends to underestimate the degree of ventricular enlargement in women [163,164]. TTE plays a crucial role in initial and surveillance imaging, providing reproducible measures of LV dimension, function, and aortic dimensions. Aortic root should be measured at 4 different levels (annulus, sinuses of Valsalva, sinotubular function, and the proximal ascending aorta). TEE should be performed when there is a high suspicion of aortic dissection, particularly when AR is present, since this will allow surgeons to plan their surgical management depending on the valve anatomy. Mechanisms of AR found in patients with type A dissection are incomplete leaflet closure due to sinotubular junction dilatation, aortic valve leaflet prolapse due to extension of the dissection into the aortic root, and prolapse of the dissection flap through the aortic valve [165]. When TTE is unable to assess the severity or mechanism of AR in other disease processes, TEE is also indicated for more accurate assessment. TEE is also invaluable in the diagnosis of endocarditis in patients with bacteremia due to its higher resolution compared to TTE [166]. Similarly, the sensitivity (87% TEE vs. 28.3% TTE) and specificity (94.6% TEE vs. 98.6% TTE) are higher for the detection of abscesses associated with endocarditis. In patients with BAV, the proximal ascending aorta can be evaluated sufficiently using TEE, but visualization of the aortic arch may be incomplete due to the blind spot in the arch view. For patients who lead an inactive lifestyle or have equivocal symptoms, exercise testing may be helpful in defining functional capacity, symptomatic response, and hemodynamic effects of exercise. Exercise testing may be warranted in asymptomatic patients with limited physical activity to evaluate functional limitations and may also provide information about changes in LV function with stress [167]. Exercise capacity has been demonstrated to be predictive of recovery of function after AV replacement [168]. However, since these studies were performed in those with diminished LV function, incremental benefit of stress imaging has not been shown to have diagnostic or prognostic value and therefore, is not recommended for routine clinical use [48].

Cardiac Magnetic Resonance Imaging Echocardiographic assessment of AR can be limited by poor image quality, variability in measuring flow diameters, and foreshortened views of the ventricle. CMR by phase-contrast velocity-encoded method allows measurement of flow velocity and instantaneous volume flow rates in the aorta or pulmonary artery; these data can be integrated over the cardiac cycle to determine the RV and fraction. CMR also allows accurate measurement of left and right ventricular volumes; the difference in stroke volume between the two ventricles in isolated AR yields the RV. Currently, CMR application is most helpful when regurgitant severity is indeterminate on

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echocardiography, when more accurate measures of LV function are required, and/or when aortic dilation is present. CMR using SSFP sequence allows good visualization of the AV in any chosen plane. Characterization of valve morphology is feasible allowing reliable differentiation between bicuspid and trileaflet AV. The signal void in diastole, representing AR, is best visualized in coronal oblique plane, but serves only as a qualitative indicator signifying presence, but not necessarily severity of AR (Figure 11.18). Magnetic resonance imaging with phase-contrast velocity-encoded measurements of blood flow velocity and volume flow is increasingly being used in clinical practice. Phase-contrast velocity encoding allows antegrade and retrograde blood flow measurement in the ascending aorta and has been validated in studies demonstrating an accuracy of 90% (Figure 11.18) [169]. Therefore, quantitative assessment of the severity of AR is possible via calculation of regurgitant volume and fraction. Flow measurement has shown good correlation to ventricular volumetric quantification of AR [170]. Throughplane imaging for velocity-encoding purpose needs to be performed proximally and perpendicular to the regurgitant orifice to overcome impediments posed by jet direction and leaflet motion. When slice distance is increased from the

17 7

aortic valve, a decrease in measured RV occurs due to an aortic compliance effect [171]. A potential limitation of phase-contrast technique is that it is less accurate with coexisting AS, necessitating a higher through-plane velocity encoding, thereby potentially affecting the AR sensitivity. Another consideration is that AR volume may be underestimated due to the upward movement of the aortic root in diastole or when the aortic root is dilated and mobile. A potential solution is anticipated, but commercial technique that tracks and adapts flow measurements to cardiac motion is currently unavailable [172]. As timing of surgery in the asymptomatic patient is dependent on the compliance properties of the left ventricle, outcome data are more favorable in patients with preserved systolic LV function. CMR is the gold standard for its accurate and reproducible LVEF, volume, and mass quantification, making it ideally suited for systolic function determination when echo-derived EF is suboptimal. Concomitantly, it reveals aortic root or proximal aorta involvement successfully differentiating between aortopathy, dissection, and arteritis. It is imaging modality of choice for a comprehensive valvular, aortic, and ventricular surveillance in bicuspid patients.

F I G U R E 1 1 . 1 8 â•… Quantification of aortic regurgitant fraction by cardiac magnetic resonance imaging. Flow volume versus time curve in the ascend-

ing aorta demonstrating regurgitant flow during isovolumic relaxation and early diastole. The regurgitant fraction is measured to be 27% (upper panel). Cine magnetic resonance imaging (MRI) using steady-state free-precession technique demonstrates the signal void consistent with a regurgitant jet (arrow) (lower left panel). Phase velocity image of proximal aorta at the level of the PA bifurcation (lower right panel).

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Cardiac Computed Tomography A routine clinical implementation of MDCT for the exclusive diagnostic evaluation of AR cannot be currently recommended at this point, due to radiation exposure and use of iodinated contrast. Nevertheless, in patients with a raised possibility of coronary artery disease and concomitant AR, direct visualization of the aortic regurgitant orifice in diastole by MDCT is feasible. When incomplete coaptation of the aortic valve leaflets during diastole is demonstrated confirming the presence of AR by CT, quantification of AR by planimetry of the anatomic regurgitant orifice is quite possible, however a TTE study is further recommended to quantify the severity of the disease. CCT has been validated against echocardiography for determining the severity of AR [74,173]. Compared with TTE, CCT has demonstrated a sensitivity of 70% and a specificity of 100%. Once AR was detected, the anatomic regurgitant orifice area assessed by MDCT was strongly associated with severity of AR as measured by VC, ratio of jet to LVOT height, and ratio of jet to LVOT crosssectional area [174]. In a patient population with degenerative aortic valve stenosis, the ability of CCT to identify AR demonstrated sensitivity of 81% and specificity of 91%; however, it was feasible in only 50% of these patients due to calcification of the cusp margins causing blurring, partial volume artifacts, and beam-hardening artifacts [173]. CCT can be instrumental in key decision making when the etiology of AR includes enlargement of the aortic root, dissection with involvement of the AV, and dilation and thickening of the aorta in inflammatory disease processes including giant cell or Takayasu’s arteritis. The effects of AR on LV chamber dimension or ejection fraction are integral in the management of patients with severe AR. LV cavity dimensions and ejection fraction measurements can be made analogous to echocardiography and have been validated against CMR [175]. The MSCT can provide detailed information on the shape of the aortic annulus, and the relation between the annulus and the ostia of the coronary arteries. Thereby, MSCT may be helpful for avoiding paravalvular leakage and coronary occlusion and may facilitate the selection of candidates for transcatheter aortic valve replacement [79].

jâ•… TRICUSPID VALVE The normal anatomy of the tricuspid valve (TV) apparatus is complex. In the normal heart, the TV has 3 leaflets: anterior, posterior, and septal [176]. The valve is attached to the atrioventricular junction of the right ventricle. The 3 leaflets are distinguished by their position—Â�septal, anterior, and posterior leaflets. The anterior leaflet is largest, posterior is multi-scalloped, and the septal leaflet is smallest. They are joined by papillary muscles; the medial papillary muscle has chordal attachments to septal and the posterior leaflets

Multimodality Imaging in Cardiovascular Medicine

while the anterior papillary muscle provides chordae to the posterior and the anterior leaflets. Comprehensive evaluation of this complex valvular apparatus still poses a challenge to all imaging modalities. Tricuspid Stenosis Isolated tricuspid stenosis (TS) is very rare and is usually part of rheumatic multivalvular disease. Although the hemodynamic lesion of TS can be tolerated for long periods of time, the majority of patients require repair [177]. The main causes of TS include rheumatic heart disease, carcinoid disease, tricuspid atresia, endocarditis, endomyocardial fibrosis, and systemic lupus erythematosus. Tricuspid Regurgitation Tricuspid regurgitation (TR) can be classified as physiologic, primary, or secondary. A small degree of physiologic TR is found on Doppler echocardiography in approximately 70% of healthy adults [178–180]. When significant TR is present with normal TV morphology, majority of the time, it is secondary or functional regurgitation caused by dilatation of the annulus resulting from increase in pulmonary or right ventricular pressure and/or right ventricular dimension in setting of pulmonary hypertension or RV infarction [181]. Tricuspid annulus is very dynamic and can change markedly with loading conditions [182]. In its normal state, the TV has a nonplanar, elliptical-shaped annulus, with the mediolateral aspect being the lowest point and the anteroseptal aspect as the highest [183]. In functional TR, the annulus becomes more planar and dilates in the septal-lateral direction, resulting in a more circular shape compared to the elliptical shape found in healthy subjects [184]. Primary TR, while less common, is due to intrinsic involvement of the TV from rheumatic causes and less commonly from endocarditis, carcinoid heart disease, leaflet prolapse, chordal or papillary muscle rupture, myxomatous degeneration, from iatrogenic sequelae such as endomyocardial biopsies, pacemaker insertion, radiation therapy, or congenital anomalies such as Ebstein’s anomaly or tricuspid atresia [161,185–187] TR is a progressive condition with involvement of the right ventricle and atrium and is associated not only with left ventricular dysfunction but also with left-sided valvular heart disease, mitral more than aortic [188–190] Moderate or greater TR is associated with increased morbidity and mortality, consequently, appropriate assessment and quantification is imperative, especially when considering left-sided or cardiac surgery in general [191,192].

Echocardiography A 2DE is the most common and widely used imaging modality for diagnosis of TV pathology. Identification of a particular leaflet is dependent on the echocardiographic view,

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F I G U R E 1 1 . 1 9 â•… Two-dimensional imaging of the tricuspid valve (TV): (A) apical 4-chamber view, (B) right ventricular inflow from a parasternal

window, (C) short-axis, (D) subcostal short-axis view, and (E) subcostal 4-chamber. Only the right ventricular inflow view demonstrates the posterior leaflet of the TV. All other views of the TV show the septal and anterior leaflets.

with posterior leaflets best visualized in parasternal short axis, and the anterior and septal leaflets consistently visualized in the apical 4-chamber views (Figure 11.19). Crucial to TR’s etiologic and prognostic assessment is the size of the right cardiac chambers, biventricular function, concomitant valvular heart disease, and associated pulmonary pressures. Color Doppler echocardiography helps confirm the diagnosis of TR by visualization in at least 2 orthogonal planes. Traditionally, qualitative methods assessing regurgitation of the TV have relied on visual estimation of the jet length to right atrial chamber dimension from the parasternal and apical views, and jet dimensions have been demonstrated to correlate well with angiographic and clinical measures of regurgitant severity [193,194]. However, jet size evaluation is limited by its dependence on hemodynamic conditions, instrument setting, and variable interaction with the right atrium [160,195,196]. Though chronically severe TR can be confirmed by right atrial, ventricular, and inferior vena cava size along with the bowing of the interatrial septum, however, these can be normal in setting of acute severe TR. Indubitably, detection of a flail leaflet is pathognomonic for severe TR. Paradoxical interventricular septal motion

while indicative of volume overload state and consistent with severe TR is not specific to regurgitation of TV [197]. Quantitative assessment of TR is emphasized, although underutilized; it involves the use of VC method and flow convergence to calculate EROA, which has been shown to correlate with other measures of TR severity such as hepatic venous flow pattern, regurgitant flow and volume, and the RA area (Figure 11.20) [198,199]. Quantification of TR using the flow convergence method is challenging, less utilized clinically, and has been validated only in small studies [151]. Retrograde flow in the vena cava and systolic reversal of flow in hepatic veins are indices of severe TR however, are susceptible to changes in RA and RV relaxation and compliance, dependent on the phase of the respiratory cycle, preload conditions, and can be influenced by atrial fibrillation [200]. TR in association with MV disease, deserves emphasis as it has a significant impact on the long-term prognosis of the patients [188,201–203]. Hence, it requires special consideration during mitral and/or aortic valve surgery. Along with the severity of TR, annulus size, a determinant of TR, is an important echocardiographic component of surgical evaluation when considering

Multimodality Imaging in Cardiovascular Medicine

18 0

Mild

Moderate

Severe

Doppler

PISA Radius

Vena Contracta

*not defined F I G U R E 1 1 . 2 0 â•… Tricuspid regurgitation (TR): grading severity of TR using continuous-wave Doppler (top panel), flow convergence using proximal

isovelocity area (PISA) (middle panel), and color Doppler using vena contracta method.

not only tricuspid but also MV repair or replacement [202,204–206]. Tricuspid annular dilation is a progressive disease that often does not resolve with correction of the left-sided lesion alone. Cardinal echocardiographic features in TS include diastolic doming, thickening, and restricted movement of the leaflets [207]. Similar to mitral stenosis, M-mode recording in TS shows decreased diastolic slope and separation of the leaflets, although these findings are nonspecific. Unlike mitral stenosis, planimetry or visualization of the stenotic orifice is not feasible via 2DE. Nevertheless, emphasis needs to be placed on presence of commissural fusion, assessment of the subvalvular apparatus, and degree of concomitant TR in patients with rheumatic TV disease [162]. Of note, unlike mitral stenosis, the degree of calcification is less pronounced. PHT and continuity equation are not applicable in TS assessment. Peak and mean velocity of the diastolic signal are used to quantitatively define the severity of the TV. While there is no standardized grading of severity, a mean pressure gradient greater than 2 mm Hg establishes the diagnosis of TS and a gradient greater than 5 mm Hg is considered significant [162]. Echocardiography remains the imaging modality of choice when diagnosing and guiding management of congenital tricuspid malformations such as Ebstein’s anomaly. The principle echocardiographic features distinguishing Ebstein’s anomaly from other tricuspid lesions include apical displacement of the septal tricuspid leaflet from the insertion of the anterior leaflet of the MV by at least .8 mm/m2, in addition to the presence of elongated tricuspid anterior

leaflet (Figure 11.21) [208]. The resultant abnormal motion of the anterior leaflet prognosticates surgical outcome [209]. RT3DE has yet to be used widely. Its use is particularly helpful in detailed morphological assessment of the TV and subvalvular apparatus, including leaflet size and thickness, relationship to other leaflets, myocardial walls, and the annular geometry [210]. While the literature is less than

F I G U R E 1 1 . 2 1 â•… Ebstein’s anomaly demonstrating the atrialization of

the right ventricle and apical displacement of the tricuspid leaflet.

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prolific on this subject, there are case reports utilizing this technology depicting visualization of tricuspid abnormalities such as TS, cleft TV, and a flail tricuspid leaflet [211]. It is feasible via 3DE to visualize the TV with all its trileaflets simultaneously allowing planimetry along with evaluation of leaflet coaptation and commissural separation (Figure 11.22) [210]. Changes in tricuspid annulus evident in functional TR, as determined by RT3DE, are stimulating mechanistic and therapeutic insights into future timing and type of intervention [183]. Mechanisms of TR severity can be more reliably discerned by 3DE including septal leaflet tethering, septal-lateral annular dilatation, or severity of pulmonary hypertension [212]. 3DE has been instrumental in elucidating the mechanism of TR resulting from pacemaker lead–related complications by identifying lead route and position as well as perforation or entrapment of tricuspid leaflet [213]. RT3DE measurements of the tricuspid annulus have been shown to be comparable to those obtained from CMR; 3DE could potentially be used for presurgical planning prior to TV annuloplasty [214]. As atrial septal defects coexist with tricuspid hemodynamic abnormalities, 3DE allows a comprehensive evaluation of not only ASD size and morphology but also its critical spatial relationship to other cardiac structures, together with right atrial and ventricular volume and function [209,215,216].

181

Cardiac Magnetic Resonance Imaging The ability to readily image the heart in any imaging plane without the use of ionizing radiation or nephrotoxic contrast material makes CMR an attractive noninvasive diagnostic modality to study right-sided cardiac structures. TR is most easily appreciated in the longitudinal cardiac axes (the 4 chamber and the coronal oblique views). Similar to MR quantification, TR can be quantified using a combination of velocity-encoded flow measurements (VENC) through the pulmonic valve and global RV stroke volume calculation made using Simpson’s method of disks in the absence of significant pulmonic regurgitation. Tricuspid RV 5 LVSV – RVSV or RVSV – pulmonary artery SV. RF is determined by dividing the tricuspid RV by the RV stroke volume (RF (%) 5 (TRV 4 RVSV) 3 100%). Through-plane VENC imaging of the tricuspid annulus can also be used to quantify TR, albeit less reliably as it is subject to inaccuracies introduced by long-axial displacement of the heart relative to the imaging plane. Cine imaging of the valve using a contiguous stack of transaxial cines followed by through-plane velocity mapping of the regurgitant jet immediately on the atrial side of the valve can delineate the cross-sectional area of the jet. This allows a qualitative assessment of the size and shape of regurgitant orifice and may serve as a qualitative adjunctive tool for severity assessment.

F I G U R E 1 1 . 2 2 â•… Three-dimensional echocardiography of the tricuspid valve shown from a right atrial perspective on the right (A and C) and from a right ventricular view (B and D). The top panels are in diastole and the bottom panels are in systole.

182

Carcinoid disease with its characteristic appearance consisting of thickened, retracted, fixed, and noncoapting leaflets with thickened subvalvular apparatus contributing to a fixed, semi-open position is classically diagnosed via echocardiography, but feasible with cardiac MRI, which may improve diagnostic accuracy when echocardiographic imaging is suboptimal (Figure 11.23). MRI may offer supplementary information on the pulmonic valve as it is involved in most cases [217]. Cardiac MRI is useful in demonstrating severe dilatation of the right atrium and ventricle that may result from TR which is further exacerbated when pulmonic stenosis is present. Reproducible assessment of right ventricular volume and function is central to the management of carcinoid disease as development of progressive dilatation and reduction in function are important factors in the decision to proceed with valve replacement. Perioperative mortality, previously estimated around 35%, can be significantly reduced by timely intervention before significant dilation of RA and ventricle can occur [218–220]. On cine MRI images, marked immobility of the tricuspid is evident throughout the cardiac cycle, leading to a fixed open position of the cusps during systole and severe TR. Ebstein’s anomaly is associated with atrialization of the right ventricle with varying degrees of TR, and possibly atrial septal defects or VSDs. Cardiac MRI not only helps quantify the degree of regurgitation but also provides unrestricted views of the atria and ventricles, the location and function of the displaced TV, the size and function of the right ventricle, and the patency of the pulmonary arteries. CMR has become a cornerstone for clinical decision-making on timing of surgical repair of TV in Ebstein patients. Although echocardiography may better define the valve leaflets, CMR has the added advantage of providing wide fields of view across the enlarged volume of the heart, thereby establishing presence of concomitant atrial septal defects along with the presence of any other shunts [221,222]. Combination of cine images, velocity-encoded imaging, and magnetic resonance angiography provides a comprehensive evaluation of tricuspid pathology, its effects on right atrium, right ventricular size and function, and presence of associated findings.

Cardiac Computed Tomography TV is usually not visualized well on standard CCT scans because right-sided structures are intentionally less opacified. However, the timing of the scan can be optimized via the use of bolus-tracking techniques to opacify the right-sided structures allowing for direct visualization of tricuspid leaflet morphology and thickening. Severity of tricuspid disease can be indirectly evaluated using CCT by ira assessment of the right heart-right atrial and ventricular size and volume, bowing of the interventricular septum to the left implying elevated right-sided pressures, and by the presence of contrast in the inferior vena cava and/or hepatic veins during first-pass contrast-enhanced CT of the

Multimodality Imaging in Cardiovascular Medicine

F I G U R E 1 1 . 2 3 â•… Carcinoid disease. In a right ventricular inflow view,

the anterior and posterior leaflets appear thickened and immobile (panel A) causing severe wide open tricuspid regurgitation shown in panel B.

chest indicating TR (unless the patient performed a valsalva maneuver during the breath hold) [38]. j â•…P ULMONIC VALVE Pulmonary valve (PV) is a semilunar valve with 3 cusps and 3 commissures. The leaflets are attached at their bases to the annulus consisting of a ring of tough, dense fibrous tissue. The crest of each leaflet is attached to the wall of the pulmonary artery. Pulmonary valve stenosis may be part of a constellation of congenital findings such as Tetralogy of Fallot, ventricular inversion, or may be found in relative isolation [223]. Hence, valvular assessment is usually incomplete without a concomitant evaluation of the right ventricle, including outflow tract and pulmonary artery. Pulmonic regurgitation (PR) in a normal individual is found in 28% to 88% of the population, becoming less frequent as one ages. Pulmonic regurgitation in its more severe form in adults is usually due to prior intervention for congenital abnormalities including Tetralogy of Fallot, Ross

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procedure, or postrepair or reconstruction of right LVOT. Pulmonary hypertension, endocarditis, carcinoid heart disease, or myxomatous valves are other causes of moderate to severe regurgitation [224,225]. The pertinent etiologic clues need to be taken into consideration when choosing the imaging modality of choice for evaluation of pulmonary regurgitation.

Echocardiography Echocardiography continues to be the mainstay and initial diagnostic study of choice for evaluation of the pulmonic valve; however, it is limited by poor acoustic windows, body habitus, and anterior location of the valve. Typically, only 2 leaflets are seen in a conventional parasternal window though all 3 leaflets may be visualized in the uncommonly used cross-sectional view. Historically, early echocardiographic findings in severe pulmonary hypertension using the M-mode were the flying W sign (Figure 11.24). While color flow and Doppler imaging are helpful in evaluating the severity of pulmonary regurgitation and stenosis, estimation of the severity of PR is usually qualitative. The presence of mild or moderate PR is not problematic; however, in severe regurgitation, color Doppler may display laminar flow that is of low velocity and is short in duration, which may be easily underestimated or missed entirely [226]. When visualized adequately, the duration of pulmonic insufficiency compared to the total diastolic period has shown good agreement between continuouswave and color Doppler echocardiography and CMR in quantifying severity of regurgitation in adult patients with repaired Tetralogy of Fallot (Figure 11.25) [227]. Echo-hemodynamic data can be derived from continuouswave Doppler interrogation of the pulmonary regurgitation jet envelope, allowing estimation of pulmonary mean as well as end-diastolic pressures. In pulmonic stenosis,

F I G U R E 1 1 . 2 4 â•… M-mode of pulmonic valve in a patient with pulmonary hypertension demonstrating the flying W sign.

F I G U R E 1 1 . 2 5 â•… Pulmonic valve in a patient with history of repaired

Tetralogy of Fallot status. The spectral Doppler signal (a) and color Doppler (b) are consistent with severe regurgitation.

characteristic echo findings include systolic doming of the pulmonic valve, valvular thickening and/or calcification, post-stenotic dilation of the main pulmonary artery, and right ventricular hypertrophy or dilation. Unlike PR, pulmonary stenosis severity is more easily classified into mild, moderate, and severe. The 2006 American College of Cardiology/American Heart Association (ACC/AHA) guidelines defined severe pulmonary stenosis as a peak jet velocity .4 m/s and peak gradient .60 mm Hg, moderate stenosis is defined as peak jet velocity of 3 to 4 m/s and peak gradient of 36 to 60 mm Hg, and mild stenosis is defined as peak velocity of less than 3 m/s with peak gradient of less than 36 mm Hg [161]. High-velocity flow can be seen in the right LVOT, pulmonic valve level or above the valve using color Doppler (Figure 11.26). While continuous-wave Doppler is helpful in estimating the peak gradient, pulse Doppler imaging is helpful in determining the level of stenosis. Although there are few specific indications for obtaining a TEE study of the PV when compared to the mitral or aortic valves, it is important to inspect it during routine examination. TEE is ideal, especially in surgical settings, to assess postsurgical complications such as paravalvular leaks or immobile leaflets; however, the orientation of the pulmonary artery in respect to the esophagus makes its evaluation challenging [228]. The pulmonic valve is best visualized in midesophageal cross-sectional view of the aortic valve and the midesophageal right ventricular outflow or inflow view. The PV and main pulmonary artery are demonstrated in a high esophageal view at the level of the aortic arch in a 90-degree angle. A transesophageal evaluation is especially useful in identifying involvement from endocarditis

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F I G U R E 1 1 . 2 6 â•… Color Doppler across the pulmonic valve demonstrat-

ing flow turbulence. The continuous Doppler spectral profile of the forward flow demonstrating high transvalvular velocity with peak gradient of 63 mmHg.

or presence of congenital malformations in the pulmonary position including absence of the pulmonary valve, presence of bicuspid or quadricuspid, and fenestrated or redundant valves. If visualized properly, a continuous-wave Doppler interrogation across the PV can be performed in the shortaxis view of the ascending aorta or via the deep transgastric views [228,229]. Overall, echocardiography, whether transthoracic or transesophageal, is a complementary tool and yields more comprehensive results when combined with another imaging modality, especially, cardiac MRI [230].

Cardiac Magnetic Resonance Imaging MRI provides excellent anatomical detail of the right ventricular chamber, right ventricular outflow, and better visualization of the PV compared to echocardiography; it is also considered the reference standard for right ventricular volumes and estimation of function. MRI studies provide accurate estimation of pulmonic regurgitation and stenosis [231–233]. Evaluation of the pulmonic valve via cardiac MRI is similar to imaging protocols used for evaluation of the aortic valve. Velocity is encoded through a plane transecting an oblique inlet and outlet view of the right ventricle, and an oblique sagittal SSFP cine aligned with the RVOT. SSFP cine sequences can detect the presence of a regurgitant jet, but since the size of the jet is sequence dependent, it is not a reliable indicator of severity of regurgitation. Phase-contrast technique is a more reliable and accurate means of quantifying regurgitation; it is performed by using a velocity-encoding range just sufficient to avoid aliasing, typically 2 m/s, but higher, if there is a suspicion of valvular or supravalvular stenosis [234,235]. Maximal velocity across the PV can be calculated by utilizing the velocity-encoding technique. Serial evaluation of congenital PV disease using MRI has been used routinely

Multimodality Imaging in Cardiovascular Medicine

as it does not subject patients to ionizing radiation or to risk of contrast-related nephropathy [236,237]. MRI may play a crucial role in determining the timing of PV surgery in both isolated cases of valvular disease, and especially in those patients with corrected Tetralogy of Fallot as it provides accurate and reproducible information on right ventricular volume, size, and function [238]. The pulmonic regurgitant orifice can be wide in the absence of effective pulmonary valve function after repair of Tetralogy of Fallot or valvotomy for congenital pulmonary stenosis. A RF of about 40% is typical in patients with no effective pulmonary valve action and can vary considerably depending on upstream and downstream factors [239,240]. Free PR does not necessarily connote severe RF of 50% or more, which would correctly be considered severe, unusual, and may be attributable to additional factors such as distal PA branch stenosis or elevated pulmonary resistance. Long-term deleterious effects of abnormal right ventricular morphology, volume, and function from severe PR are predictors of ventricular arrhythmia and irreversible right ventricular remodeling. Therefore, MRI is an optimal study in this patient population, potentially at risk for sudden cardiac death [241–244].

Cardiac Computed Tomography CCT imaging has not been traditionally used for assessment of pulmonic valvular pathology. It has played a stronger role in noninvasive coronary imaging, especially in settings of congenital disease involving anomalous coronaries and/or great arteries which can coexist with pulmonic valve pathology. CT compared to cardiac MRI with its shorter acquisition time, easy accessibility along with its capability of providing volumetric and morphologic information on pertinent cardiac structures makes it a desirable preoperative or postoperative imaging modality in congenital patients [245]. Similar to MRI, it can play a complementary role to echocardiography in detecting morphologic and leaflet motion abnormalities, including valvular thickening and abnormal cusp excursion and apposition. In addition, it offers indirect measures of valvular pathology, including right ventricular enlargement due to chronic volume overload in the presence of severe pulmonary regurgitation and pulmonary trunk dilatation in pulmonic stenosis. Other features appreciated on CT that can be informative of severity of pulmonic valve disease include bowing of the interventricular septum to the left, which in diastole is indicative of pressure overload and in systole indicative of volume overload, and contrast reflux into the inferior vena cava and hepatic veins suggestive of secondary TR [38]. However, the ionizing radiation and use of contrast preclude its use in certain patient populations and make it less than ideal in its application as a serial imaging modality especially, in the younger patient population.

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jâ•… REFERENCES â•‡â•‡ 1. Wood P. Disease of the Heart and Circulation. 2nd ed. London: Eyre & Spottiswoode; 1956. â•‡â•‡ 2. Bland EF, Jones TD. The natural history of rheumatic fever: a 20 year perspective. Ann Intern Med. 1952;37(5):1006–1026. â•‡â•‡ 3. Newsholme A. The Milroy lectures on the natural history and affinities of rheumatic fever: a study in epidemiology. Lancet. 1895;1:589–592. â•‡â•‡ 4. Cutler E, Levine SA. Cardiotomy and valvulotomy for mitral stenosis: experimental observations and clinical notes concerning an operated case with recovery. Boston Med Surg J. 1923;188:1023. â•‡â•‡ 5. Edler I, Hertz HC. Use of ultrasonic reflectoscope for the continuous recording of the movements of heart walls. Kunglia Fysiogr Sallsk I Lund Frohandl. 1954;24:1–19. â•‡â•‡ 6. Gross L, Kugel MA. Topographic anatomy and histology of the valves in the human heart. Am J Pathol. 1931;7(5):445–474. â•‡â•‡ 7. Lam JH, Ranganathan N, Wigle ED, Silver MD. Morphology of the human mitral valve. I. Chordae tendineae: a new classification. Circulation. 1970;41(3):449–458. â•‡â•‡ 8. Wilkins GT, Weyman AE, Abascal VM, Block PC, Palacios IF. Percutaneous balloon dilatation of the mitral valve: an analysis of echocardiographic variables related to outcome and the mechanism of dilatation. Br Heart J. 1988;60(4):299–308. â•‡â•‡ 9. Nishimura RA, Rihal CS, Tajik AJ, Holmes DR Jr. Accurate measurement of the transmitral gradient in patients with mitral stenosis: a simultaneous catheterization and Doppler echocardiographic study. J Am Coll Cardiol. 1994;24(1):152–158. â•‡ 10. Hatle L, Brubakk A, Tromsdal A, Angelsen B. Noninvasive assessment of pressure drop in mitral stenosis by Doppler ultrasound. Br Heart J. 1978;40(2):131–140. â•‡ 11. Nakatani S, Masuyama T, Kodama K, Kitabatake A, Fujii K, Kamada T. Value and limitations of Doppler echocardiography in the quantification of stenotic mitral valve area: comparison of the pressure half-time and the continuity equation methods. Circulation. 1988;77(1):78–85. â•‡ 12. Smith MD, Wisenbaugh T, Grayburn PA, Gurley JC, Spain MG, DeMaria AN. Value and limitations of Doppler pressure half-time in quantifying mitral stenosis: a comparison with micromanometer catheter recordings. Am Heart J. 1991;121(2, pt 1):480–8. â•‡ 13. Braverman AC, Thomas JD, Lee RT. Doppler echocardiographic estimation of mitral valve area during changing hemodynamic conditions. Am J Cardiol. 1991;68(15):1485–1490. â•‡ 14. Karp K, Teien D, Bjerle P, Eriksson P. Reassessment of valve area determinations in mitral stenosis by the pressure half-time method: impact of left ventricular stiffness and peak diastolic pressure difference. J Am Coll Cardiol. 1989;13(3):594–599. â•‡ 15. Rodriguez L, Thomas JD, Monterroso V, et al. Validation of the proximal flow convergence method. Calculation of orificeÂ� area in patients with mitral stenosis. Circulation. 1993;88(3):1157–1165. â•‡ 16. Bennis A, Drighil A, Tribouilloy C, Drighil A, Chraibi N. Clinical application in routine practice of the proximal flow convergence method to calculate the mitral surface area in mitral valve stenosis. Int J of Cardiovasc Imaging. 2002;18(6):443–451. â•‡ 17. Rifkin RD, Harper K, Tighe D. Comparison of proximal isovelocityÂ� surface area method with pressure half-time and planimetryÂ� in evaluationÂ� of mitral stenosis. J Am Coll Cardiol. 1995;26(2):458–465. â•‡ 18. Martin RP, Rakowski H, Kleiman JH, Beaver W, London E, Popp RL. Reliability and reproducibility of two-dimensional echocardiograph measurement of the stenotic mitral valve orifice area. Am J Cardiol. 1979;43(3):560–568. â•‡ 19. Binder TM, Rosenhek R, Porenta G, Maurer G, Baumgartner H. Improved assessment of mitral valve stenosis by volumetric realtime three-dimensional echocardiography. J Am Coll Cardiol. 2000;36(4):1355–1361. â•‡ 20. Chen Q, Nosir YF, Vletter WB, Kint PP, Salustri A, Roelandt JR. Accurate assessment of mitral valve area in patients with

â•‡ 21.

â•‡ 22.

â•‡ 23.

â•‡ 24.

â•‡ 25.

â•‡ 26.

â•‡ 27.

â•‡ 28.

â•‡ 29.

â•‡ 30.

â•‡ 31.

â•‡ 32.

â•‡ 33.

â•‡ 34.

â•‡ 35.

â•‡ 36.

â•‡ 37.

â•‡ 38.

â•‡ 39.

â•‡ 40.

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mitral stenosis by three-dimensional echocardiography. J Am Soc Echocardiogr. 1997;10(2):133–140. Sugeng L, Weinert L, Lammertin G, et al. Accuracy of mitral valve area measurements using transthoracic rapid freehand 3-dimensional scanning: comparison with noninvasive and invasive methods. J Am Soc Echocardiogr. 2003;16(12):1292–1300. Sebag IA, Morgan JG, Handschumacher MD, et al. Usefulness of three-dimensionally guided assessment of mitral stenosis using matrix-array ultrasound. Am J Cardiol. 2005;96(8):1151–1156. Zamorano J, Cordeiro P, Sugeng L, et al. Real-time threedimensional echocardiography for rheumatic mitral valve stenosis evaluation: an accurate and novel approach. J Am Coll Cardiol. 2004;43(11):2091–2096. Zamorano J, Perez de Isla L, Sugeng L, et al. Non-invasive assessment of mitral valve area during percutaneous balloon mitral valvuloplasty: role of real-time 3D echocardiography. Eur Heart J. 2004;25(23):2086–2091. Fernandez-Reyes MJ, Auxiliadora Bajo M, Robles P, et al. Mitral annular calcification in CAPD patients with a low degree of hyperparathyroidism. An analysis of other possible risk factors. Nephrol Dial Transplant. 1995;10(11):2090–2095. Fox CS, Vasan RS, Parise H, et al. Mitral annular calcification predicts cardiovascular morbidity and mortality: the Framingham Heart Study. Circulation. 2003;107(11):1492–1496. Sari I, Davutoglu V. Relationship between mitral annular calcificationÂ� and renal impairment: what is the link? Int J Cardiol. 2009;133(1):114, author reply 5. Schott CR, Kotler MN, Parry WR, Segal BL. Mitral annular calcification. Clinical and echocardiographic correlations. Arch Intern Med. 1977;137(9):1143–1150. Jesri A, Braitman LE, Pressman GS. Severe mitral annular calcification predicts chronic kidney disease. Int J Cardiol. 2008;128(2):193–196. Ix JH, Shlipak MG, Katz R, et al. Kidney function and aortic valve and mitral annular calcification in the multi-ethnic study of atherosclerosis (MESA). Am J Kidney Dis. 2007;50(3):412–420. Rao AK, Djamali A, Korcarz CE, Aeschlimann SE, Wolff MR, Stein JH. Mitral annular calcification is associated with reduced left ventricular function and inflammation in patients with chronic kidney disease. J Am Soc Echocardiogr. 2008;21(6):747–750. Willens HJ, Chirinos JA, Schob A, Veerani A, Perez AJ, Chakko S. The relation between mitral annular calcification and mortality in patients undergoing diagnostic coronary angiography. Echocardiography. 2006;23(9):717–722. Sharma R, Pellerin D, Gaze DC, et al. Mitral annular calcification predicts mortality and coronary artery disease in end stage renal disease. Atherosclerosis. 2007;191(2):348–354. Chu JW, Levine RA, Chua S, et al. Assessing mitral valve area and orifice geometry in calcific mitral stenosis: a new solution by realtime three-dimensional echocardiography. J Am Soc Echocardiogr. 2008;21(9):1006–1009. Djavidani B, Debl K, Lenhart M, et al. Planimetry of mitral valve stenosis by magnetic resonance imaging. J Am Coll Cardiol. 2005;45(12):2048–2053. Heidenreich PA, Steffens J, Fujita N, et al. Evaluation of mitral stenosis with velocity-encoded cine-magnetic resonance imaging. Am J Cardiol. 1995;75(5):365–369. Lin SJ, Brown PA, Watkins MP, et al. Quantification of stenotic mitral valve area with magnetic resonance imaging and comparison with Doppler ultrasound. J Am Coll Cardiol. 2004;44(1):133–137. Manghat NE, Rachapalli V, Van Lingen R, Veitch AM, Roobottom CA, Morgan-Hughes GJ. Imaging the heart valves using ECG-gated 64-detector row cardiac CT. Br J Radiol. 2008;81(964):275–290. Alkadhi H, Bettex D, Wildermuth S, et al. Dynamic cine imaging of the mitral valve with 16-MDCT: a feasibility study. AJR Am J Roentgenol. 2005;185(3):636–646. Messika-Zeitoun D, Serfaty JM, Laissy JP, et al. Assessment of the mitral valve area in patients with mitral stenosis by multislice computed tomography. J Am Coll Cardiol. 2006;48(2):411–413.

Multimodality Imaging in Cardiovascular Medicine

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â•‡ 41. Konen E, Goitein O, Feinberg MS, et al. The role of ECG-gated MDCT in the evaluation of aortic and mitral mechanical valves: initial experience. AJR Am J Roentgenol. 2008;191(1):26–31. â•‡ 42. Teshima H, Hayashida N, Fukunaga S, et al. Usefulness of a multidetector-row computed tomography scanner for detecting pannus formation. Ann Thorac Surg. 2004;77(2):523–526. â•‡ 43. Carpentier A, Chauvaud S, Fabiani JN, et al. Reconstructive surgeryÂ� of mitral valve incompetence: ten-year appraisal. J Thorac Cardiovasc Surg. 1980;79(3):338–348. â•‡ 44. Iung B, Baron G, Butchart EG, et al. A prospective survey of patients with valvular heart disease in Europe: the Euro heart survey on valvular heart disease. Eur Heart J. 2003;24(13):1231–1243. â•‡ 45. Olson LJ, Subramanian R, Ackermann DM, Orszulak TA, Edwards WD. Surgical pathology of the mitral valve: a study of 712 cases spanning 21 years. Mayo Clin Proc. 1987;62(1):22–34. â•‡ 46. Marcus RH, Sareli P, Pocock WA, Barlow JB. The spectrum of severe rheumatic mitral valve disease in a developing countryÂ�. Correlations among clinical presentation, surgical pathologic findings, and hemodynamic sequelae. Ann Intern Med. 1994;120(3):177–183. â•‡ 47. Tantchou Tchoumi JC, Butera G. Rheumatic valvulopathies occurrence, pattern and follow-up in rural area: the experience of the Shisong Hospital, Cameroon. Bull Soc Pathol Exot. 2009;102(3):155–158. â•‡ 48. Bonow RO, Carabello BA, Chatterjee K, et al. 2008 focused update incorporated into the ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to revise the 1998 guidelines for the management of patients with valvular heart disease). Endorsed by the Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol. 2008;52(13):e1–e142. â•‡ 49. Agricola E, Oppizzi M, De Bonis M, et al. Multiplane transesophageal echocardiography performed according to the guidelines of the American Society of Echocardiography in patients with mitral valve prolapse, flail, and endocarditis: diagnostic accuracy in the identification of mitral regurgitant defects by correlation with surgical findings. J Am Soc Echocardiogr. 2003;16(1):61–66. â•‡ 50. Grewal KS, Malkowski MJ, Kramer CM, Dianzumba S, Reichek N. Multiplane transesophageal echocardiographic identification of the involved scallop in patients with flail mitral valve leaflet: intraoperative correlation. J Am Soc Echocardiogr. 1998;11(10):966–971. â•‡ 51. Omran AS, Woo A, David TE, Feindel CM, Rakowski H, Siu SC. Intraoperative transesophageal echocardiography accurately predicts mitral valve anatomy and suitability for repair. J Am Soc Echocardiogr. 2002;15(9):950–957. â•‡ 52. Levine RA, Handschumacher MD, Sanfilippo AJ, et al. Threedimensional echocardiographic reconstruction of the mitral valve, with implications for the diagnosis of mitral valve prolapse. Circulation. 1989;80(3):589–598. â•‡ 53. Chauvel C, Bogino E, Clerc P, et al. Usefulness of three-dimensional echocardiography for the evaluation of mitral valve prolapse: an intraoperative study. J Heart Valve Dis. 2000;9(3):341–349. â•‡ 54. Delabays A, Jeanrenaud X, Chassot PG, Von Segesser LK, Kappenberger L. Localization and quantification of mitral valve prolapse using three-dimensional echocardiography. Eur J Echocardiogr. 2004;5(6):422–429. â•‡ 55. Muller S, Muller L, Laufer G, et al. Comparison of three-dimensional imaging to transesophageal echocardiography for preoperative evaluation in mitral valve prolapse. Am J Cardiol. 2006;98(2):243–248. â•‡ 56. Pepi M, Tamborini G, Maltagliati A, et al. Head-to-head comparison of two- and three-dimensional transthoracic and transesophageal echocardiography in the localization of mitral valve prolapse. J Am Coll Cardiol. 2006;48(12):2524–2530. â•‡ 57. Otsuji Y, Handschumacher MD, Liel-Cohen N, et al. Mechanism of ischemic mitral regurgitation with segmental left ventricular

â•‡ 58.

â•‡ 59.

â•‡ 60.

â•‡ 61.

â•‡ 62.

â•‡ 63.

â•‡ 64.

â•‡ 65.

â•‡ 66.

â•‡ 67.

â•‡ 68.

â•‡ 69.

â•‡ 70.

â•‡ 71.

â•‡ 72.

â•‡ 73.

â•‡ 74.

â•‡ 75.

dysfunction: three-dimensional echocardiographic studies in models of acute and chronic progressive regurgitation. J Am Coll Cardiol. 2001;37(2):641–648. Kahlert P, Plicht B, Schenk IM, Janosi RA, Erbel R, Buck T. Direct assessment of size and shape of noncircular vena contracta area in functional versus organic mitral regurgitation using real-time three-dimensional echocardiography. J Am Soc Echocardiogr. 2008;21(8):912–921. Little SH, Pirat B, Kumar R, et al. Three-dimensional color Doppler echocardiography for direct measurement of vena contracta area in mitral regurgitation: in vitro validation and clinical experience. JACC Cardiovasc Imaging. 2008;1(6):695–704. Sugeng L, Weinert L, Lang RM. Real-time 3-dimensional color Doppler flow of mitral and tricuspid regurgitation: feasibility and initial quantitative comparison with 2-dimensional methods. J Am Soc Echocardiogr. 2007;20(9):1050–1057. Yosefy C, Hung J, Chua S, et al. Direct measurement of vena contracta area by real-time 3-dimensional echocardiography for assessing severity of mitral regurgitation. Am J Cardiol. 2009;104(7):978–983. O’Gara P, Sugeng L, Lang R, et al. The role of imaging in chronic degenerative mitral regurgitation. JACC Cardiovasc Imaging. 2008;1(2):221–237. Chan KM, Wage R, Symmonds K, et al. Towards comprehensive assessment of mitral regurgitation using cardiovascular magnetic resonance. J Cardiovasc Magn Reson. 2008;10(1):61. Gabriel RS, Kerr AJ, Raffel OC, Stewart RA, Cowan BR, Occleshaw CJ. Mapping of mitral regurgitant defects by cardiovascular magnetic resonance in moderate or severe mitral regurgitation secondary to mitral valve prolapse. J Cardiovasc Magn Reson. 2008;10(1):16. Stork A, Franzen O, Ruschewski H, et al. Assessment of functional anatomy of the mitral valve in patients with mitral regurgitation with cine magnetic resonance imaging: comparison with transesophageal echocardiography and surgical results. Eur Radiol. 2007;17(12):3189–3198. Gelfand EV, Hughes S, Hauser TH, et al. Severity of mitral and aortic regurgitation as assessed by cardiovascular magnetic resonance: optimizing correlation with Doppler echocardiography. J Cardiovasc Magn Reson. 2006;8(3):503–507. Higgins CB, Wagner S, Kondo C, Suzuki J, Caputo GR. Evaluation of valvular heart disease with cine gradient echo magnetic resonance imaging. Circulation. 1991;84(3)(suppl):I198–I207. Kon MW, Myerson SG, Moat NE, Pennell DJ. Quantification of regurgitant fraction in mitral regurgitation by cardiovascular magnetic resonance: comparison of techniques. J Heart Valve Dis. 2004;13(4):600–607. Kayser HW, Stoel BC, van der Wall EE, van der Geest RJ, de Roos A. MR velocity mapping of tricuspid flow: correction for throughplane motion. J Magn Reson Imaging. 1997;7(4):669–673. Westenberg JJ, Roes SD, Ajmone Marsan N, et al. Mitral valve and tricuspid valve blood flow: accurate quantification with 3D velocity-encoded MR imaging with retrospective valve tracking. Radiology. 2008;249(3):792–800. Buchner S, Debl K, Poschenrieder F, et al. Cardiovascular magnetic resonance for direct assessment of anatomic regurgitant orifice in mitral regurgitation. Circ Cardiovasc Imaging. 2008;1(2):148–155. Guo YK, Yang ZG, Ning G, et al. Sixty-four-slice multidetector computed tomography for preoperative evaluation of left ventricular function and mass in patients with mitral regurgitation: comparison with magnetic resonance imaging and echocardiography. Eur Radiol. 2009;19(9):2107–2116. Guo YK, Yang ZG, Ning G, et al. Isolated mitral regurgitation: quantitative assessment with 64-section multidetector CT-comparison with MR imaging and echocardiography. Radiology. 2009;252(2):369–376. Alkadhi H, Wildermuth S, Bettex DA, et al. Mitral regurgitation: quantification with 16-detector row CT—initial experience. Radiology. 2006;238(2):454–463. Maselli D, Guarracino F, Chiaramonti F, Mangia F, Borelli G, Minzioni G. Percutaneous mitral annuloplasty: an anatomic study

C HA P TER 11

â•‡ 76.

â•‡ 77.

â•‡ 78.

â•‡ 79.

â•‡ 80.

â•‡ 81.

â•‡ 82.

â•‡ 83.

â•‡ 84.

â•‡ 85.

â•‡ 86. â•‡ 87.

â•‡ 88.

â•‡ 89.

â•‡ 90.

â•‡ 91.

â•‡ 92.

â•‡ 93.

â•‡ 94.

•

Multimodality Imaging in Valvular Heart Disease

of human coronary sinus and its relation with mitral valve annulus and coronary arteries. Circulation. 2006;114(5):377–380. Tops LF, Van de Veire NR, Schuijf JD, et al. Noninvasive evaluation of coronary sinus anatomy and its relation to the mitral valve annulus: implications for percutaneous mitral annuloplasty. Circulation. 2007;115(11):1426–1432. Doddamani S, Grushko MJ, Makaryus AN, et al. Demonstration of left ventricular outflow tract eccentricity by 64-slice multi-detector CT. Int J Cardiovas Imaging. 2009;25(2):175–181. Poh KK, Levine RA, Solis J, et al. Assessing aortic valve area in aortic stenosis by continuity equation: a novel approach using real-time three-dimensional echocardiography. Eur Heart J. 2008;29(20):2526–2535. Tops LF, Wood DA, Delgado V, et al. Noninvasive evaluation of the aortic root with multislice computed tomography implications for transcatheter aortic valve replacement. JACC Cardiovasc Imaging. 2008;1(3):321–330. Piazza N, de Jaegere P, Schultz C, Becker AE, Serruys PW, Anderson RH. Anatomy of the aortic valvar complex and its implications for transcatheter implantation of the aortic valve. Circ Cardiovasc Interv. 2008;1(1):74–81. Lang RM, Bierig M, Devereux RB, et al. Recommendations for chamber quantification: a report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr. 2005;18(12):1440–1463. Aronow WS, Kronzon I. Prevalence and severity of valvular aortic stenosis determined by Doppler echocardiography and its association with echocardiographic and electrocardiographic left ventricular hypertrophy and physical signs of aortic stenosis in elderly patients. Am J Cardiol. 1991;67(8):776–777. Lindroos M, Kupari M, Heikkila J, Tilvis R. Prevalence of aortic valve abnormalities in the elderly: an echocardiographic study of a random population sample. J Am Coll Cardiol. 1993;21(5):1220–1225. Roberts WC, Ko JM. Frequency by decades of unicuspid, bicuspid, and tricuspid aortic valves in adults having isolated aortic valve replacement for aortic stenosis, with or without associated aortic regurgitation. Circulation. 2005;111(7):920–925. Freeman RV, Otto CM. Spectrum of calcific aortic valve disease: pathogenesis, disease progression, and treatment strategies. Circulation. 2005;111(24):3316–3326. Rosenhek R, Binder T, Porenta G, et al. Predictors of outcome in severe, asymptomatic aortic stenosis. N Engl J Med. 2000;343(9):611–617. Murdoch JL, Walker BA, Halpern BL, Kuzma JW, McKusick VA. Life expectancy and causes of death in the Marfan syndrome. N Engl J Med. 1972;286(15):804–808. Fedak PW, Verma S, David TE, Leask RL, Weisel RD, Butany J. Clinical and pathophysiological implications of a bicuspid aortic valve. Circulation. 2002;106(8):900–904. Hahn RT, Roman MJ, Mogtader AH, Devereux RB. Association of aortic dilation with regurgitant, stenotic and functionally normal bicuspid aortic valves. J Am Coll Cardiol. 1992;19(2):283–288. Januzzi JL, Isselbacher EM, Fattori R, et al. Characterizing the young patient with aortic dissection: results from the International Registry of Aortic Dissection (IRAD). J Am Coll Cardiol. 2004;43(4):665–669. Roberts CS, Roberts WC. Dissection of the aorta associated with congenital malformation of the aortic valve. J Am Coll Cardiol. 1991;17(3):712–716. Russo CF, Mazzetti S, Garatti A, et al. Aortic complications after bicuspid aortic valve replacement: long-term results. Ann Thorac Surg. 2002;74(5):S1773–S1776. Baumgartner H, Hung J, Bermejo J, et al. Echocardiographic assessment of valve stenosis: EAE/ASE recommendations for clinical practice. J Am Soc Echocardiogr. 2009;22(1):1–23. Oh JK, Taliercio CP, Holmes DR, Jr., et al. Prediction of the severity of aortic stenosis by Doppler aortic valve area determination:

â•‡ 95.

â•‡ 96.

â•‡ 97.

â•‡ 98.

â•‡ 99.

100.

101.

102.

103.

104.

105.

106.

107.

108.

109. 110.

111. 112.

113.

114.

115.

187

prospective Doppler-catheterization correlation in 100 patients. J Am Coll Cardiol. 1988;11(6):1227–1234. Zoghbi WA, Farmer KL, Soto JG, Nelson JG, Quinones MA. Accurate noninvasive quantification of stenotic aortic valve area by Doppler echocardiography. Circulation. 1986;73(3):452–459. Otto CM, Burwash IG, Legget ME, et al. Prospective study of asymptomatic valvular aortic stenosis. Clinical, echocardiographic, and exercise predictors of outcome. Circulation. 1997;95(9):2262–2270. Rosenhek R, Klaar U, Schemper M, et al. Mild and moderate aortic stenosis. Natural history and risk stratification by echocardiography. Eur Heart J. 2004;25(3):199–205. Okura H, Yoshida K, Hozumi T, Akasaka T, Yoshikawa J. Planimetry and transthoracic two-dimensional echocardiography in noninvasive assessment of aortic valve area in patients with valvular aortic stenosis. J Am Coll Cardiol. 1997;30(3):753–759. Nistri S, Galderisi M, Faggiano P, et al. Practical echocardiography in aortic valve stenosis. J Cardiovasc Med. (Hagerstown) 2008;9(7): 653–665. Garcia D, Pibarot P, Landry C, et al. Estimation of aortic valve effective orifice area by Doppler echocardiography: effects of valve inflow shape and flow rate. J Am Soc Echocardiogr. 2004;17(7):756–765. Berglund H, Kim CJ, Nishioka T, Luo H, Siegel RJ. Influence of ejection fraction and valvular regurgitation on the accuracy of aortic valve area determination. Echocardiography. 2001;18(1):65–72. Danielsen R, Nordrehaug JE, Vik-Mo H. Factors affecting Doppler echocardiographic valve area assessment in aortic stenosis. Am J Cardiol. 1989;63(15):1107–1111. deFilippi CR, Willett DL, Brickner ME, et al. Usefulness of dobutamine echocardiography in distinguishing severe from nonsevere valvular aortic stenosis in patients with depressed left ventricular function and low transvalvular gradients. Am J Cardiol. 1995;75(2):191–194. Monin JL, Quere JP, Monchi M, et al. Low-gradient aortic stenosis: operative risk stratification and predictors for long-term outcome: a multicenter study using dobutamine stress hemodynamics. Circulation. 2003;108(3):319–324. Nishimura RA, Grantham JA, Connolly HM, Schaff HV, Higano ST, Holmes DR Jr. Low-output, low-gradient aortic stenosis in patients with depressed left ventricular systolic function: the clinical utility of the dobutamine challenge in the catheterization laboratory. Circulation. 2002;106(7):809–813. Cormier B, Iung B, Porte JM, Barbant S, Vahanian A. Value of multiplane transesophageal echocardiography in determining aortic valve area in aortic stenosis. Am J Cardiol. 1996;77(10):882–885. Sochowski RA, Chan KL. Implication of negative results on a monoplane transesophageal echocardiographic study in patients with suspected infective endocarditis. J Am Coll Cardiol. 1993;21(1):216–221. Moss RR, Ivens E, Pasupati S, et al. Role of echocardiography in percutaneous aortic valve implantation. JACC Cardiovasc Imaging. 2008;1(1):15–24. Larson EW, Edwards WD. Risk factors for aortic dissection: a necropsy study of 161 cases. Am J Cardiol. 1984;53(6):849–855. Nistri S, Basso C, Marzari C, Mormino P, Thiene G. Frequency of bicuspid aortic valve in young male conscripts by echocardiogram. Am J Cardiol 2005;96(5):718–721. Roberts WC. The congenitally bicuspid aortic valve. A study of 85 autopsy cases. Am J Cardiol 1970;26(1):72–83. Steinberger J, Moller JH, Berry JM, Sinaiko AR. Echocardiographic diagnosis of heart disease in apparently healthy adolescents. Pediatrics. 2000;105(4, pt 1):815–888. Pachulski RT, Weinberg AL, Chan KL. Aortic aneurysm in patients with functionally normal or minimally stenotic bicuspid aortic valve. Am J Cardiol 1991;67(8):781–782. Clementi M, Notari L, Borghi A, Tenconi R. Familial congenital bicuspid aortic valve: a disorder of uncertain inheritance. Am J Med Genet. 1996;62(4):336–338. Cotrufo M, Della Corte A, De Santo LS, et al. Different patterns of extracellular matrix protein expression in the convexity and the

18 8

concavity of the dilated aorta with bicuspid aortic valve: preliminary results. J Thorac Cardiovasc Surg. 2005;130(2):504–11. 116. Huntington K, Hunter AG, Chan KL. A prospective study to assess the frequency of familial clustering of congenital bicuspid aortic valve. J Am Coll Cardiol. 1997;30(7):1809–1812. 117. Kupfahl C, Honold M, Meinhardt G, et al. Evaluation of aortic stenosis by cardiovascular magnetic resonance imaging: comparison with established routine clinical techniques. Heart. 2004;90(8):893–901. 118. Pouleur AC, le Polain de Waroux JB, Pasquet A, Vancraeynest D, Vanoverschelde JL, Gerber BL. Planimetric and continuity equation assessment of aortic valve area: head to head comparison between cardiac magnetic resonance and echocardiography. J Magn Reson Imaging. 2007;26(6):1436–1443. 119. Otto CM. Valvular aortic stenosis: disease severity and timing of intervention. J Am Coll Cardiol. 2006;47(11):2141–2151. 120. Gleeson TG, Mwangi I, Horgan SJ, Cradock A, Fitzpatrick P, Murray JG. Steady-state free-precession (SSFP) cine MRI in distinguishing normal and bicuspid aortic valves. J Magn Reson Imaging. 2008;28(4):873–878. 121. Kilner PJ, Manzara CC, Mohiaddin RH, et al. Magnetic resonance jet velocity mapping in mitral and aortic valve stenosis. Circulation. 1993;87(4):1239–1248. 122. O’Brien KR, Gabriel RS, Greiser A, Cowan BR, Young AA, Kerr AJ. Aortic valve stenotic area calculation from phase contrast cardiovascular magnetic resonance: the importance of short echo time. J Cardiovasc Magn Reson. 2009;11(1):49. 123. Caruthers SD, Lin SJ, Brown P, et al. Practical value of cardiac magnetic resonance imaging for clinical quantification of aortic valve stenosis: comparison with echocardiography. Circulation. 2003;108(18):2236–2243. 124. Haghi D, Papavassiliu T, Kalmar G, et al. A hybrid approach for quantification of aortic valve stenosis using cardiac magnetic resonance imaging and echocardiography. J Cardiovasc Magn Reson. 2005;7(3):581–586. 125. Alkadhi H, Wildermuth S, Plass A, et al. Aortic stenosis: comparative evaluation of 16-detector row CT and echocardiography. Radiology. 2006;240(1):47–55. 126. LaBounty TM, Sundaram B, Agarwal P, Armstrong WA, Kazerooni EA, Yamada E. Aortic valve area on 64-MDCT correlates with transesophageal echocardiography in aortic stenosis. AJR Am J Roentgenol. 2008;191(6):1652–1658. 127. Gilon D, Cape EG, Handschumacher MD, et al. Effect of threedimensional valve shape on the hemodynamics of aortic stenosis: three-dimensional echocardiographic stereolithography and patient studies. J Am Coll Cardiol. 2002;40(8):1479–1486. 128. Halpern EJ, Mallya R, Sewell M, Shulman M, Zwas DR. Differences in aortic valve area measured with CT planimetry and echocardiography (continuity equation) are related to divergent estimates of left ventricular outflow tract area. AJR Am J Roentgenol. 2009;192(6):1668–1673. 129. Koos R, Mahnken AH, Sinha AM, Wildberger JE, Hoffmann R, Kuhl HP. Aortic valve calcification as a marker for aortic stenosis severity: assessment on 16-MDCT. AJR Am J Roentgenol. 2004;183(6):1813–1818. 130. Messika-Zeitoun D, Aubry MC, Detaint D, et al. Evaluation and clinical implications of aortic valve calcification measured by electron-beam computed tomography. Circulation. 2004;110(3):356–362. 131. Ruhl KM, Das M, Koos R, et al. Variability of aortic valve calcification measurement with multislice spiral computed tomography. Invest Radiol. 2006;41(4):370–373. 132. Schoenhagen P, Tuzcu EM, Kapadia SR, Desai MY, Svensson LG. Three-dimensional imaging of the aortic valve and aortic root with computed tomography: new standards in an era of transcatheter valve repair/implantation. Eur Heart J. 2009;30(17):2079–2086. 133. Wood DA, Tops LF, Mayo JR, et al. Role of multislice computed tomography in transcatheter aortic valve replacement. Am J Cardiol. 2009;103(9):1295–1301.

Multimodality Imaging in Cardiovascular Medicine

134. Ng AC, Delgado V, van der Kley F, et al. Comparison of aortic root dimensions and geometries pre- and post-transcatheter aortic valve implantation by 2- and 3-dimensional transesophageal echocardiography and multi-slice computed tomography. Circ Cardiovasc Imaging. 2009. 135. Tsai IC, Lin YK, Chang Y, et al. Correctness of multi-detector-row computed tomography for diagnosing mechanical prosthetic heart valve disorders using operative findings as a gold standard. Eur Radiol. 2009;19(4):857–867. 136. Symersky P, Budde RP, de Mol BA, Prokop M. Comparison of multidetector-row computed tomography to echocardiography and fluoroscopy for evaluation of patients with mechanical prosthetic valve obstruction. Am J Cardiol. 2009;104(8):1128–1134. 137. LaBounty TM, Agarwal PP, Chughtai A, Bach DS, Wizauer E, Kazerooni EA. Evaluation of mechanical heart valve size and function with ECG-gated 64-MDCT. AJR Am J Roentgenol. 2009;193(5):W389–W396. 138. LaBounty TM, Agarwal PP, Chughtai A, Kazerooni EA, Wizauer E, Bach DS. Hemodynamic and functional assessment of mechanical aortic valves using combined echocardiography and multidetector computed tomography. J Cardiovasc Comput Tomogr. 2009;3(3):161–167. 139. Flohr T, Stierstorfer K, Raupach R, Ulzheimer S, Bruder H. Performance evaluation of a 64-slice CT system with z-flying focal spot. Rofo. 2004;176(12):1803–1810. 140. Pellikka PA, Nishimura RA, Bailey KR, Tajik AJ. The natural history of adults with asymptomatic, hemodynamically significant aortic stenosis. J Am Coll Cardiol.1990;15(5):1012–1017. 141. Guiney TE, Davies MJ, Parker DJ, Leech GJ, Leatham A. The aetiology and course of isolated severe aortic regurgitation: a clinical, pathological, and echocardiographic study. Br Heart J. 1987;58(4): 358–368. 142. Michel PL, Acar J, Chomette G, Iung B. Degenerative aortic regurgitation. Eur Heart J. 1991;12(8):875–882. 143. Olson LJ, Subramanian R, Edwards WD. Surgical pathology of pure aortic insufficiency: a study of 225 cases. Mayo Clin Proc. 1984;59(12):835–841. 144. Roberts WC, Morrow AG, McIntosh CL, Jones M, Epstein SE. Congenitally bicuspid aortic valve causing severe, pure aortic regurgitation without superimposed infective endocarditis. Analysis of 13 patients requiring aortic valve replacement. Am J Cardiol. 1981;47(2):206–209. 145. Tarasoutchi F, Grinberg M, Spina GS, et al. Ten-year clinical laboratory follow-up after application of a symptom-based therapeutic strategy to patients with severe chronic aortic regurgitation of predominant rheumatic etiology. J Am Coll Cardiol. 2003;41(8):1316–1324. 146. Waller BF, Howard J, Fess S. Pathology of aortic valve stenosis and pure aortic regurgitation: a clinical morphologic assessment— Part II. Clin Cardiol. 1994;17(3):150–156. 147. Waller BF, Taliercio CP, Dickos DK, Howard J, Adlam JH, Jolly W. Rare or unusual causes of chronic, isolated, pure aortic regurgitation. Clin Cardiol. 1990;13(8):577–581. 148. El Khoury G, Glineur D, Rubay J, et al. Functional classification of aortic root/valve abnormalities and their correlation with etiologies and surgical procedures. Curr Opin Cardiol. 2005;20(2):115–121. 149. Maurer G. Aortic regurgitation. Heart. 2006;92(7):994–1000. 150. Bekeredjian R, Grayburn PA. Valvular heart disease: aortic regurgitation. Circulation. 2005;112(1):125–134. 151. Zoghbi WA, Enriquez-Sarano M, Foster E, et al. Recommendations for evaluation of the severity of native valvular regurgitation with two-dimensional and Doppler echocardiography. J Am Soc Echocardiogr. 2003;16(7):777–802. 152. Meyer T, Sareli P, Pocock WA, Dean H, Epstein M, Barlow J. Echocardiographic and hemodynamic correlates of diastolic closure of mitral valve and diastolic opening of aortic valve in severe aortic regurgitation. Am J Cardiol. 1987;59(12):1144–1148. 153. Winsberg F, Gabor GE, Hernberg JG, Weiss B. Fluttering of the mitral valve in aortic insufficiency. Circulation. 1970;41(2):225–229.

C HA P TER 11

•

Multimodality Imaging in Valvular Heart Disease

154. Tribouilloy CM, Enriquez-Sarano M, Fett SL, Bailey KR, Seward JB, Tajik AJ. Application of the proximal flow convergence method to calculate the effective regurgitant orifice area in aortic regurgitation. J Am Coll Cardiol. 1998;32(4):1032–1039. 155. Tribouilloy CM, Enriquez-Sarano M, Bailey KR, Seward JB, Tajik AJ. Assessment of severity of aortic regurgitation using the width of the vena contracta: a clinical color Doppler imaging study. Circulation. 2000;102(5):558–564. 156. Willett DL, Hall SA, Jessen ME, Wait MA, Grayburn PA. Assessment of aortic regurgitation by transesophageal color Doppler imaging of the vena contracta: validation against an intraoperative aortic flow probe. J Am Coll Cardiol. 2001;37(5):1450–1455. 157. Perry GJ, Helmcke F, Nanda NC, Byard C, Soto B. Evaluation of aortic insufficiency by Doppler color flow mapping. J Am Coll Cardiol. 1987;9(4):952–959. 158. Teague SM, Heinsimer JA, Anderson JL, et al. Quantification of aortic regurgitation utilizing continuous wave Doppler ultrasound. J Am Coll Cardiol. 1986;8(3):592–599. 159. Masuyama T, Kodama K, Kitabatake A, et al. Noninvasive evaluation of aortic regurgitation by continuous-wave Doppler echocardiography. Circulation. 1986;73(3):460–466. 160. Taylor AL, Eichhorn EJ, Brickner ME, Eberhart RC, Grayburn PA. Aortic valve morphology: an important in vitro determinant of proximal regurgitant jet width by Doppler color flow mapping. J Am Coll Cardiol. 1990;16(2):405–412. 161. Bonow RO, Carabello BA, Kanu C, et al. ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing committee to revise the 1998 Guidelines for the Management of Patients With Valvular Heart Disease): developed in collaboration with the Society of Cardiovascular Anesthesiologists: endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons. Circulation. 2006;114(5):e84–e231. 162. Vahanian A, Baumgartner H, Bax J, et al. Guidelines on the management of valvular heart disease: the Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology. Eur Heart J. 2007;28(2):230–268. 163. Klodas E, Enriquez-Sarano M, Tajik AJ, Mullany CJ, Bailey KR, Seward JB. Aortic regurgitation complicated by extreme left ventricular dilation: long-term outcome after surgical correction. J Am Coll Cardiol. 1996;27(3):670–677. 164. Sambola A, Tornos P, Ferreira-Gonzalez I, Evangelista A. Prognostic value of preoperative indexed end-systolic left ventricle diameter in the outcome after surgery in patients with chronic aortic regurgitation. Am Heart J. 2008;155(6):1114–1120. 165. Movsowitz HD, Levine RA, Hilgenberg AD, Isselbacher EM. Transesophageal echocardiographic description of the mechanisms of aortic regurgitation in acute type A aortic dissection: implications for aortic valve repair. J Am Coll Cardiol. 2000;36(3):884–890. 166. Shively BK, Gurule FT, Roldan CA, Leggett JH, Schiller NB. Diagnostic value of transesophageal compared with transthoracic echocardiography in infective endocarditis. J Am Coll Cardiol. 1991;18(2):391–397. 167. Borer JS, Hochreiter C, Herrold EM, et al. Prediction of indications for valve replacement among asymptomatic or minimally symptomatic patients with chronic aortic regurgitation and normal left ventricular performance. Circulation. 1998;97(6):525–534. 168. Wahi S, Haluska B, Pasquet A, Case C, Rimmerman CM, Marwick TH. Exercise echocardiography predicts development of left ventricular dysfunction in medically and surgically treated patients with asymptomatic severe aortic regurgitation. Heart. 2000;84(6):606–614. 169. Dulce MC, Mostbeck GH, O’Sullivan M, Cheitlin M, Caputo GR, Higgins CB. Severity of aortic regurgitation: interstudy reproducibility of measurements with velocity-encoded cine MR imaging. Radiology. 1992;185(1):235–240. 170. Sondergaard L, Lindvig K, Hildebrandt P, et al. Quantification of aortic regurgitation by magnetic resonance velocity mapping. Am Heart J. 1993;125(4):1081–1090.

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171. Chatzimavroudis GP, Walker PG, Oshinski JN, Franch RH, Pettigrew RI, Yoganathan AP. Slice location dependence of aortic regurgitation measurements with MR phase velocity mapping. Magn Reson Med. 1997;37(4):545–551. 172. Kozerke S, Schwitter J, Pedersen EM, Boesiger P. Aortic and mitral regurgitation: quantification using moving slice velocity mapping. J Magn Reson Imaging. 2001;14(2):106–112. 173. Feuchtner GM, Dichtl W, Schachner T, et al. Diagnostic performance of MDCT for detecting aortic valve regurgitation. AJR Am J Roentgenol.2006;186(6):1676–1681. 174. Jassal DS, Shapiro MD, Neilan TG, et al. 64-slice multidetector computed tomography (MDCT) for detection of aortic regurgitation and quantification of severity. Invest Radiol. 2007;42(7):507–512. 175. Raman SV, Shah M, McCarthy B, Garcia A, Ferketich AK. Multidetector row cardiac computed tomography accurately quantifies right and left ventricular size and function compared with cardiac magnetic resonance. Am Heart J. 2006;151(3):736–744. 176. Lamers WH, Viragh S, Wessels A, Moorman AF, Anderson RH. Formation of the tricuspid valve in the human heart. Circulation. 1995;91(1):111–121. 177. Roguin A, Rinkevich D, Milo S, Markiewicz W, Reisner SA. Longterm follow-up of patients with severe rheumatic tricuspid stenosis. Am Heart J. 1998;136(1):103–108. 178. Jobic Y, Slama M, Tribouilloy C, et al. Doppler echocardiographic evaluation of valve regurgitation in healthy volunteers. Br Heart J. 1993;69(2):109–113. 179. Lavie CJ, Hebert K, Cassidy M. Prevalence and severity of Dopplerdetected valvular regurgitation and estimation of right-sided cardiac pressures in patients with normal two-dimensional echocardiograms.Â� Chest. 1993;103(1):226–231. 180. Singh JP, Evans JC, Levy D, et al. Prevalence and clinical determinants of mitral, tricuspid, and aortic regurgitation (the Framingham Heart Study). Am J Cardiol. 1999;83(6):897–902. 181. Waller BF, Howard J, Fess S. Pathology of tricuspid valve stenosis and pure tricuspid regurgitation—Part III. Clin Cardiol. 1995;18(4):225–230. 182. Rogers JH, Bolling SF. The tricuspid valve: current perspective and evolving management of tricuspid regurgitation. Circulation. 2009;119(20):2718–2725. 183. Ton-Nu TT, Levine RA, Handschumacher MD, et al. Geometric determinants of functional tricuspid regurgitation: insights from 3-dimensional echocardiography. Circulation. 2006;114(2):143–149. 184. Fukuda S, Saracino G, Matsumura Y, et al. Three-dimensional geometry of the tricuspid annulus in healthy subjects and in patients with functional tricuspid regurgitation: a real-time, 3-dimensional echocardiographic study. Circulation. 2006;114(1) (suppl):I492–I498. 185. Chan MC, Giannetti N, Kato T, et al. Severe tricuspid regurgitation after heart transplantation. J Heart Lung Transplant. 2001;20(7):709–717. 186. King RM, Schaff HV, Danielson GK, et al. Surgery for tricuspid regurgitation late after mitral valve replacement. Circulation. 1984;70(3, pt 2):I193–I197. 187. Simon R, Oelert H, Borst HG, Lichtlen PR. Influence of mitral valve surgery on tricuspid incompetence concomitant with mitral valve disease. Circulation. 1980;62(2, pt 2):I152–I157. 188. Boyaci A, Gokce V, Topaloglu S, Korkmaz S, Goksel S. Outcome of significant functional tricuspid regurgitation late after mitral valve replacement for predominant rheumatic mitral stenosis. Angiology. 2007;58(3):336–342. 189. Izumi C, Iga K, Konishi T. Progression of isolated tricuspid regurgitation late after mitral valve surgery for rheumatic mitral valve disease. J Heart Valve Dis. 2002;11(3):353–356. 190. Porter A, Shapira Y, Wurzel M, et al. Tricuspid regurgitation late after mitral valve replacement: clinical and echocardiographic evaluation. J Heart Valve Dis. 1999;8(1):57–62. 191. Hung J, Koelling T, Semigran MJ, Dec GW, Levine RA, Di Salvo TG. Usefulness of echocardiographic determined tricuspid regurgitation in predicting event-free survival in severe heart failure secondary to idiopathic-dilated cardiomyopathy or to ischemic cardiomyopathy. Am J Cardiol.1998;82(10):1301–1303, A10.

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192. Nath J, Foster E, Heidenreich PA. Impact of tricuspid regurgitation on long-term survival. J Am Coll Cardiol. 2004;43(3):405–409. 193. Gonzalez Vilchez F, Zarauza J, Martin Duran R, et al. The estimation of the severity of tricuspid insufficiency by Doppler color: the effects of gain, pulse repetition frequency and the echographic view. Rev Esp Cardiol. 1994;47(7):439–449. 194. Shapira Y, Porter A, Wurzel M, Vaturi M, Sagie A. Evaluation of tricuspid regurgitation severity: echocardiographic and clinical correlation. J Am Soc Echocardiogr. 1998;11(6):652–659. 195. Bolger AF, Eigler NL, Maurer G. Quantifying valvular regurgitation. Limitations and inherent assumptions of Doppler techniques. Circulation. 1988;78(5, pt 1):1316–1318. 196. Cape EG, Yoganathan AP, Weyman AE, Levine RA. Adjacent solid boundaries alter the size of regurgitant jets on Doppler color flow maps. J Am Coll Cardiol. 1991;17(5):1094–1102. 197. Miyatake K, Okamoto M, Kinoshita N, et al. Evaluation of tricuspid regurgitation by pulsed Doppler and two-dimensional echocardiography. Circulation. 1982;66(4):777–784. 198. Tribouilloy CM, Enriquez-Sarano M, Bailey KR, Tajik AJ, Seward JB. Quantification of tricuspid regurgitation by measuring the width of the vena contracta with Doppler color flow imaging: a clinical study. J Am Coll Cardiol. 2000;36(2):472–478. 199. Yoganathan AP, Cape EG, Sung HW, Williams FP, Jimoh A. Review of hydrodynamic principles for the cardiologist: applications to the study of blood flow and jets by imaging techniques. J Am Coll Cardiol. 1988;12(5):1344–1353. 200. Nagueh SF, Kopelen HA, Zoghbi WA. Relation of mean right atrial pressure to echocardiographic and Doppler parameters of right atrial and right ventricular function. Circulation. 1996;93(6):1160–1169. 201. Groves PH, Lewis NP, Ikram S, Maire R, Hall RJ. Reduced exerciseÂ� capacity in patients with tricuspid regurgitation after successful mitral valve replacement for rheumatic mitral valve disease. Br Heart J. 1991;66(4):295–301. 202. Matsunaga A, Duran CM. Progression of tricuspid regurgitation after repaired functional ischemic mitral regurgitation. Circulation. 2005;112(9) (suppl):I453–I457. 203. Sagie A, Freitas N, Chen MH, Marshall JE, Weyman AE, Levine RA. Echocardiographic assessment of mitral stenosis and its associated valvular lesions in 205 patients and lack of association with mitral valve prolapse. J Am Soc Echocardiogr. 1997;10(2):141–148. 204. Dreyfus GD, Corbi PJ, Chan KM, Bahrami T. Secondary tricuspid regurgitation or dilatation: which should be the criteria for surgical repair? Ann Thorac Surg. 2005;79(1):127–132. 205. Duran CM, Pomar JL, Colman T, Figueroa A, Revuelta JM, Ubago JL. Is tricuspid valve repair necessary? J Thorac Cardiovasc Surg. 1980;80(6):849–860. 206. McCarthy PM, Bhudia SK, Rajeswaran J, et al. Tricuspid valve repair: durability and risk factors for failure. J Thorac Cardiovasc Surg. 2004;127(3):674–685. 207. Feigenbaum H, Armstrong WF, Ryan T. Feigenbaum’s Echocardiography. 6th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2004. 208. Edwards WD. Embryology and pathologic features of Ebstein’s anomaly. Progr Pediatr Cardiol. 1993;2(2):11. 209. Paranon S, Acar P. Ebstein’s anomaly of the tricuspid valve: from fetus to adult: congenital heart disease. Heart. 2008;94(2):237–243. 210. Anwar AM, Geleijnse ML, Soliman OI, McGhie JS, Nemes A, ten Cate FJ. Evaluation of rheumatic tricuspid valve stenosis by real-time three-dimensional echocardiography. Heart. 2007;93(3):363–364. 211. Faletra F, La Marchesina U, Bragato R, De Chiara F. Three dimensional transthoracic echocardiography images of tricuspid stenosis. Heart. 2005;91(4):499. 212. Park YH, Song JM, Lee EY, Kim YJ, Kang DH, Song JK. Geometric and hemodynamic determinants of functional tricuspid regurgitation: a real-time three-dimensional echocardiography study. Int J Cardiol. 2008;124(2):160–165. 213. Seo Y, Ishizu T, Nakajima H, Sekiguchi Y, Watanabe S, Aonuma K. Clinical utility of 3-dimensional echocardiography in the evaluation of tricuspid regurgitation caused by pacemaker leads. Circ J. 2008;72(9):1465–1470.

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214. Anwar AM, Geleijnse ML, Soliman OI, et al. Assessment of normal tricuspid valve anatomy in adults by real-time three-Â�dimensional echocardiography. Int J Cardiovasc Imaging. 2007;23(6): 717–724. 215. Pandian NG, Nanda NC, Schwartz SL, et al. Three-dimensional and four-dimensional transesophageal echocardiographic imaging of the heart and aorta in humans using a computed tomographic imaging probe. Echocardiography. 1992;9(6):677–687. 216. Roelandt JR, ten Cate FJ, Vletter WB, Taams MA. Ultrasonic dynamic three-dimensional visualization of the heart with a multiplane transesophageal imaging transducer. J Am Soc Echocardiogr. 1994;7(3, pt 1):217–229. 217. Pellikka PA, Tajik AJ, Khandheria BK, et al. Carcinoid heart disease. Clinical and echocardiographic spectrum in 74 patients. Circulation. 1993;87(4):1188–1196. 218. Castillo JG, Filsoufi F, Rahmanian PB, et al. Early and late results of valvular surgery for carcinoid heart disease. J Am Coll Cardiol. 2008;51(15):1507–1509. 219. Connolly HM, Schaff HV, Mullany CJ, Abel MD, Pellikka PA. Carcinoid heart disease: impact of pulmonary valve replacement in right ventricular function and remodeling. Circulation. 2002;106(12)(suppl 1):I51–I56. 220. Sandmann H, Pakkal M, Steeds R. Cardiovascular magnetic resonance imaging in the assessment of carcinoid heart disease. Clin Radiol. 2009;64(8):761–766. 221. Beerepoot JP, Woodard PK. Case 71: Ebstein anomaly. Radiology. 2004;231(3):747–751. 222. Didier D, Ratib O, Beghetti M, Oberhaensli I, Friedli B. Morphologic and functional evaluation of congenital heart disease by magnetic resonance imaging. J Magn Reson Imaging. 1999;10(5):639–655. 223. Brickner ME, Hillis LD, Lange RA. Congenital heart disease in adults. First of two parts. N Engl J Med. 2000;342(4):256–263. 224. Chaturvedi RR, Redington AN. Pulmonary regurgitation in congenital heart disease. Heart. 2007;93(7):880–889. 225. Himelman RB, Schiller NB. Clinical and echocardiographic comparison of patients with the carcinoid syndrome with and without carcinoid heart disease. Am J Cardiol. 1989;63(5):347–352. 226. Sorrell VL, Altbach MI, Kudithipudi V, Squire SW, Goldberg SJ, Klewer SE. Cardiac MRI is an important complementary tool to Doppler echocardiography in the management of patients with pulmonary regurgitation. Echocardiography. 2007;24(3):316–328. 227. Li W, Davlouros PA, Kilner PJ, et al. Doppler-echocardiographic assessment of pulmonary regurgitation in adults with repaired tetralogy of Fallot: comparison with cardiovascular magnetic resonance imaging. Am Heart J. 2004;147(1):165–172. 228. Joyce JJ, Hwang EY, Wiles HB, Kline CH, Bradley SM, Crawford FA Jr. Reliability of intraoperative transesophageal echocardiography during Tetralogy of Fallot repair. Echocardiography. 2000;17(4):319–327. 229. Chazouilleres AF, Foster E, Redberg RF, Schiller NB. Right ventricular outflow tract obstruction: augmented diagnosis with biplane transesophageal echocardiography. Am Heart J. 1993;126(2):477–480. 230. Hirsch R, Kilner PJ, Connelly MS, Redington AN, St John Sutton MG, Somerville J. Diagnosis in adolescents and adults with congenital heart disease. Prospective assessment of individual and combined roles of magnetic resonance imaging and transesophageal echocardiography. Circulation. 1994;90(6):2937–2951. 231. Frigiola A, Redington AN, Cullen S, Vogel M. Pulmonary regurgitation is an important determinant of right ventricular contractile dysfunction in patients with surgically repaired tetralogy of Fallot. Circulation. 2004;110(11) (suppl 1):II153–II157. 232. Rebergen SA, Chin JG, Ottenkamp J, van der Wall EE, de Roos A. Pulmonary regurgitation in the late postoperative follow-up of tetralogy of Fallot. Volumetric quantitation by nuclear magnetic resonance velocity mapping. Circulation. 1993;88(5, pt 1):2257–2266. 233. Tulevski, II, Hirsch A, Dodge-Khatami A, Stoker J, van der Wall EE, Mulder BJ. Effect of pulmonary valve regurgitation on right ventricular function in patients with chronic right ventricular pressure overload. Am J Cardiol. 2003;92(1):113–116.

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234. Meier D, Maier S, Bosiger P. Quantitative flow measurements on phantoms and on blood vessels with MR. Magn Reson Med. 1988;8(1):25–34. 235. Rebergen SA, van der Wall EE, Doornbos J, de Roos A. Magnetic resonance measurement of velocity and flow: technique, validation, and cardiovascular applications. Am Heart J. 1993;126(6):1439–1456. 236. Grothues F, Moon JC, Bellenger NG, Smith GS, Klein HU, Pennell DJ. Interstudy reproducibility of right ventricular volumes, function, and mass with cardiovascular magnetic resonance. Am Heart J. 2004;147(2):218–223. 237. Oosterhof T, Mulder BJ, Vliegen HW, de Roos A. Cardiovascular magnetic resonance in the follow-up of patients with corrected tetralogy of Fallot: a review. Am Heart J. 2006;151(2):265–72. 238. Therrien J, Provost Y, Merchant N, Williams W, Colman J, Webb G. Optimal timing for pulmonary valve replacement in adults after tetralogy of Fallot repair. Am J Cardiol. 2005;95(6):779–782. 239. Redington AN. Determinants and assessment of pulmonary regurgitation in tetralogy of Fallot: practice and pitfalls. Cardiol Clin. 2006;24(4):631–639, vii. 240. Kilner PJ, Gatehouse PD, Firmin DN. Flow measurement by magnetic resonance: a unique asset worth optimising. J Cardiovasc Magn Reson. 2007;9(4):723–728.

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241. Gatzoulis MA,Till JA, Somerville J, Redington AN. Mechanoelectrical interaction in tetralogy of Fallot. QRS prolongation relates to right ventricular size and predicts malignant ventricular arrhythmias and sudden death. Circulation. 1995;92(2):231–237. 242. Harrison DA, Harris L, Siu SC, et al. Sustained ventricular tachycardia in adult patients late after repair of tetralogy of Fallot. J Am Coll Cardiol. 1997;30(5):1368–1373. 243. Marie PY, Marcon F, Brunotte F, et al. Right ventricular overload and induced sustained ventricular tachycardia in operatively “repaired” tetralogy of Fallot. Am J Cardiol. 1992;69(8):785–789. 244. Zahka KG, Horneffer PJ, Rowe SA, et al. Long-term valvular function after total repair of tetralogy of Fallot. Relation to ventricular arrhythmias. Circulation. 1988;78(5, pt 2):III14–III19. 245. Haramati LB, Glickstein JS, Issenberg HJ, Haramati N, Crooke GA. MR imaging and CT of vascular anomalies and connections in patients with congenital heart disease: significance in surgical planning. Radiographics. 2002;22(2):337–347, discussion 48–49.

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Aortic Dissection

CHRISTOPHER J. FRANÇOIS BE NjAMI N R. LANDGRAf TH ORSTEN A . B lEY

The wall of the aorta is composed of 3 layers, the intima, media, and adventitia, and is less than 3 mm in thickness. Disruption of these layers can lead to the development of intramural hematomas (IMHs), penetrating atherosclerotic ulcers (PAUs), or aortic dissections [1–9]. Because of the common clinical presentation and shared risk factors for these entities, they are often considered together as part of acute aortic syndromes (AAS) [10].

(Figure 12.1). Blood flows into the false lumen via a proximal tear through the intima and exits through a second, distal intimal tear. The most proximal tear is frequently referred to as the entry tear, whereas more distal tears are designated exit or reentry tears. Disruption of the media without an identifiable tear in the intima is referred to as an IMH. An IMH (Figure 12.2) is thought to occur as a result of 2 possible mechanisms including spontaneous hemorrhage of the aortic vasa Â�vasorum [2,8,12]. Alternatively, an IMH can arise when an atherosclerotic ulcer penetrates into the aortic wall Â�causing hemorrhage within the media. IMH associated with a PAU tends to have a higher association with progression [13].

jâ•… DEFINITIONS

jâ•…E PI DEMIOLOGY AND PATH OPHYSIOLOGY

Aortic dissection occurs when the media is disrupted, causing a separation between the intima and adventitia [11]. This separation forms a false lumen that splits down the media and is separated from the true lumen by the intima

Population studies suggest that the incidence of aortic dissection is approximately 3/100 000 people per year [14,15]. Risk factors for aortic dissection are associated with inherited or acquired diseases that cause weakening of the aortic media.

F ig U R e 1 2 . 1 â•… Contrast-enhanced computed tomography angiography (CTA) demonstrates differential enhancement of the two lumina in a patient

with Stanford type A aortic dissection. The true lumen is readily revealed by its bright contrast (solid arrows) due to prompt arterial filling. The false lumen displays low attenuation due to slow inflow of contrast material (asterisks).

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F ig u r e 1 2 . 2 â•…Transversal contrast-enhanced computed tomography (CT) images of the thoracic aorta demonstrate low attenuation aortic wall thickening in a patient with intramural hematoma (arrows).

This leads to increased wall shear stress and accelerated aortic dilatation that eventually results in intramural hemorrhage, aortic dissection, or rupture. Although aortic dissections can occur in patients with aortic aneurysms and aortic dilatation can occur in patients with aortic dissection, approximately 80% of patients with aortic dissection do not have an aortic aneurysm at the time of presentation. The most common risk factors and conditions associated with aortic dissection have recently been published by the International Registry of Acute Aortic Dissection (IRAD) [16–21]. The most common risk factors for aortic dissection include a prior history of hypertension, increasing age (.70 years), and atherosclerosis. Aortic dissections are also more commonly seen in patients with prior cardiovascular surgery including coronary artery bypass surgery, aortic or mitral valve surgery, and aortic aneurysm or dissection repair. Less commonly associated risk factors, which are seen more often in younger patients, include the presence of a bicuspid aortic valve, aortic coarctation, aortitis, connective tissue disorders (such as Marfan syndrome, Ehlers-Danlos syndrome, relapsing polychondritis, and systemic lupus erythematosus), and pregnancy [21–25]. Interestingly, studies have shown that the association between bicuspid aortic valve, aortic dilatation, and aortic dissection is related to an acquired deficiency of aortic fibrillin, upregulation of matrix metalloproteinase, and apoptosis of vascular smooth muscle cell [26]. Aortic dissections can also occur iatrogenically or following trauma. Iatrogenic causes include prior aortic surgery, angioplasty, cardiac catheterization, and even cardio-Â�pulmonary resuscitation [27–29]. Traumatic aortic dissections are usually related to acceleration/deceleration injuries from motor vehicle accidents and can result in partial or complete disruption

of the aortic wall. With complete aortic transection, patients usually die very rapidly from exsanguination. However, if the rupture is contained by the adventitia or periadventitial soft tissues, the patients may survive long enough to present to the emergency department. Such injuries can occur in any location (Figure 12.3) but most commonly in locations where the aorta is tethered by other anatomic structures, such as the aortic root, ligamentum arteriosum, and hiatus of the diaphragm. As such, the most common locations for trauma are the aortic root (usually fatal from resulting hemopericardium and tamponade), just distal to the left subclavian artery at the junction of the aortic arch and descending thoracic aorta, and less commonly at the distal descending thoracic aorta at the diaphragmatic hiatus. As a result of the tear in the aortic wall, a pseudoaneurysm typically forms in patients who survive the initial injury (Figure 12.4). The initiating event in a dissection is a tear of the intima of the aortic wall, leading to a hemorrhage into the medial layer of the aortic wall. The intimal tear usually follows degeneration of the elastic tissue and smooth muscle cells within the media [30]. The location of the intimal tear is in the ascending aorta (Figure 12.5) in approximately 65% patients, a few centimeters above the aortic valve. The tear can also initiate in the aortic arch (10%) and descending aorta just distal to the ligamentum arteriosum (20%) [5]. Alternatively, a dissection occurs as result of an evolving IMH. Left untreated, the IMH can weaken the aortic wall followed by rupture of either the adventitia or the intima, leading to an aortic dissection [31]. Once the tear in the intima occurs, high pressure in the aortic lumen forces blood to enter the medial layer of the aortic wall. Blood flow then propagates the dissection very rapidly, most commonly in an antegrade

19 4 Multimodality Imaging in Cardiovascular Medicine

F ig u r e 1 2 . 3 â•…Oblique sagittal (A) and transversal (B) balanced steady-state free precession MR and volume rendering (C) reveal the Stanford type B aortic intimal flap (arrows in A and B). The dissection originates in the aortic arch (arrowhead in C), distal to the left subclavian artery.

F ig u r e 1 2 . 4 â•… (A) Time-resolved imaging of contrast kinetics (TRICKS) magnetic resonance angiography (MRA) demonstrates early filling of the true

lumen (solid arrows) and later filling of the false lumen (open arrows) in a patient with Stanford type B dissection. Contrast opacification in the main pulmonary artery (arrowhead) occurs before that in the aorta. (B) High-resolution 3D contrast-enhanced MRA image in the same patient shows less enhancement of the false lumen (open arrow) than that in the true lumen (closed arrows).

direction, extending the newly created false lumen distally along the aorta. Less commonly, the dissection progresses in a retrograde direction [7]. In either case, an intimal flap is created separating the true and false lumens. Identification of an intimal flap, which is usually composed of intima and portions of the media, confirms the diagnosis of an aortic dissection [10]. The intimal flap often spirals as it extends along the aorta as a result

of the torsion in blood (Figure 12.6). Reentry, or exit, tears occur anywhere along the length of the dissection, resulting in communication between the true and false lumina. Exit tears frequently occur at locations of branch arteries such as the aortic or iliac bifurcations. Alternatively, the dissection can cause a rupture through the adventitia, resulting in cardiac tamponade, hemothorax, or mediastinal hematoma [7].

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F ig u r e 1 2 . 5 â•… (A) Chest radiograph in a patient with an ascending aortic aneurysm and a Stanford type A aortic dissection showing mediastinal widening (double-sided arrow) and tracheal displacement to the right (dotted line). (B) Contrast-enhanced computed tomography angiography in the same patient demonstrates the intimal flap arising from the aortic root (arrows).

F ig u r e 1 2 . 6 â•… Transversal (A) contrast-enhanced computed tomography angiography and sagittal oblique multiplanar reformat (B) in a patient

with Stanford type B aortic dissection. The intimal flap spirals as it extends along the aorta. The proximal false lumen is thrombosed (solid arrows), whereas the distal false lumen is patent (open arrow).

jâ•… P RESENTATION Patients with AAS often present with severe, acute chest and/or back pain, characterized as sharp, tearing, ripping, often the worst-ever chest pain. However, pain may be absent in up to 10% of patients [11]. Chest pain is more common when the dissection involves the ascending aorta, whereas back pain and abdominal pain are more common

when the dissection is confined to the descending aorta. Hypotension is seen in one-fourth of patients with dissections of the ascending aorta [11,32], whereas hypertension is more common in those with descending aortic dissections [11,33]. Other clinical presentations include syncope, cardiac tamponade, stroke, absent pulses, migratory pain, neurological deficit, aortic regurgitation, cardiac failure, and abdominal pain [11].

19 6 Multimodality Imaging in Cardiovascular Medicine

1 2 . 7 â•… Transversal Â�contrastenhanced computed tomography angiography images of a patient with Stanford type A aortic dissection reveal extension of the dissection into the brachiocephalic artery (closed arrowhead). The true lumen (solid arrows) is denser than the false lumen (asterisks) on these arterial phase images. Please note mural thickening of the descending thoracic aorta consistent with intramural hematoma (open arrow). The dissection extends into the common iliac arteries bilaterally (open arrowheads).

F ig u r e

jâ•… CLA SSIFICATION Aortic dissections can be classified according to the portion of the aorta affected [34,35] or based on the underlying pathological process [36]. The Svensson classification [36] differentiates dissections based on the process separating the layers of the aortic wall. The 2 anatomically based classifications are the Stanford and DeBakey classifications. In the DeBakey classification, there are 3 types of aortic dissection [35]. DeBakey type I dissections originate in the ascending aorta and extend to involve the arch and descending aorta. DeBakey type II dissections affect the ascending aorta only, without aortic arch involvement.

DeBakey type III dissections affect the descending aorta only; type IIIA are confined to the thoracic aorta, and type IIIB extend into the abdominal aorta and iliac arteries. In the Stanford classification, there are 2 types of aortic dissection [34]. Stanford type A dissections (Figure 12.7) involve the ascending aorta, whereas Stanford type B dissections (Figure 12.8) involve the aorta distal to the ascending aorta. Stanford type A dissections may or may not extend into the arch or descending aorta. Stanford type B dissections begin distal to the origin of the brachiocephalic artery. The Stanford classification tends to be the most widely used system clinically because of the main consideration from a management perspective, that is, whether the ascending aorta is involved.

F ig u r e 1 2 . 8 â•… (A) Chest radiograph of a patient with Stanford type B aortic dissection reveals mediastinal widening (arrow). (B and C)

Corresponding contrast-enhanced computed tomography angiography images demonstrate an entry tear (arrowhead) and extension into the superior mesenteric artery (arrow). The right renal artery is supplied from the true lumen (open arrow).

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jâ•… TR EATMENT Management of dissections depends upon, most importantly, whether or not the ascending aorta is involved. Patients with IMH and PAU are treated the same as patients with classic aortic dissections. Stanford type A dissections have a high rate of mortality, particularly when the patients are older ($70 years of age) or when there is pericardial tamponade, involvement of the coronary arteries, stroke, renal failure, or pulse deficits. As a result, these types of dissections are almost always treated with surgery, because the surgical risks are outweighed by complications of the dissections [34,35,37–39]. Although many surgical techniques are used to repair the ascending aorta, the goal of surgical repair is to prevent aortic rupture and tamponade as well as to treat aortic regurgitation, if present. The prognosis of patients with Stanford type B dissections, while serious, is generally better than type A dissections, and the surgical risk is generally considered greater than the resulting complications of type B dissections. Indications for surgery in patients with type B dissections are for the prevention of life-threatening complications such as aortic rupture, limb and organ ischemia, dissection progression, aneurysm growth, and intractable pain. In most patients, type B dissections are frequently Â�managed expectantly with medical therapy [33,40–44]. Beta-blockers are the primary agent for the medical management of aortic dissections through reduction of blood pressure and, more importantly, through reduction of systolic aortic pressure through reduced myocardial contractility. Because pain is often a contributing factor in the patient’s hypertension, effective pain control is also necessary. Definitive repair of type B dissections can be performed with open

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surgical repair [45,46] and increasingly through endovascular approaches with covered stent-grafts [47–51].

jâ•… DIA GNOSTIC FEATUR ES In evaluating patients with AAS, several important imaging characteristics need to be assessed to assist in determining appropriate management. Diagnostic imaging is used to identify the intimal tear, if present, and to differentiate an aortic dissection from an IMH or PAU. Imaging features of IMH and PAU will be discussed below. Once the presence of an aortic dissection has been established, it is critical to evaluate the proximal extent of the dissection to determine if the ascending aorta is involved. Other imaging features that are important in aortic dissection include differentiation of the true and false lumina, localization of communications between the 2 lumina, delineation of the distal dissection extent, assessment of branch vessel involvement, measurement of aorta size, and detection of associated complications (such as aortic regurgitation, aortic rupture, end-organ ischemia, or infarction) [52]. Differentiation of Aortic Dissection from IMH and PAU The presence of an intimal flap with well-defined entry and exit tears, separating the true lumen from the false lumen, is what differentiates an aortic dissection from IMH and PAU. In patients with IMH, imaging studies will reveal a crescent-shaped or circular area of wall thickening without an entry tear or intimal flap (Figure 12.9). The IMH will appear hyperdense on computed tomography (CT). The signal intensity characteristics of an IMH with magnetic

F ig u r e 1 2 . 9 â•… (A) Transversal noncontrast computed tomography (CT) image reveals increased attenuation within the descending aortic wall, con-

sistent with intramural hematoma. Centrally displaced calcifications are a recognized feature of intramural hematoma (open arrow). (B) The intramural hematoma does not seem enhanced on the contrast-enhanced CT angiography image.

19 8 Multimodality Imaging in Cardiovascular Medicine

F ig u r e 1 2 . 1 0 â•… MR images in patient with Stanford type B aortic dissection. The false lumen (closed arrows) is hypointense on the steady-state

free precession (left) images, hyperintense on the T2-weighted (middle) and T1-weighted double inversion recovery (right) images because of slow flow relative to the true lumen (open arrow).

resonance imaging (MRI), however, depend upon the age of the hematoma and the current state of hemoglobin during the natural evolution of the hematoma (Figure 12.10). In the acute setting, the IMH will be hypointense on T1-weighted sequences and hyperintense on T2-weighted sequences. In the subacute setting, the IMH will be hyperintense on T1-weighted sequences as well. If the false lumen of an aortic dissection has completely thrombosed, it can be difficult to differentiate an aortic dissection from an IMH [10]. Because of the similar clinical presentation and prognosis, patients with IMH are usually treated using the same management techniques as for aortic dissection [12,53]. A PAU occurs when an atherosclerotic plaque ulcerates and extends through the intimal layer of the aorta [54]. Exposure of the medial layer of the aortic wall then causes the media to hemorrhage, which allows one to differentiate a PAU from a simple atherosclerotic plaque (Figure 12.11). A PAU almost always occurs in the mid and distal descending thoracic aorta and does not propagate longitudinally or compromise branch vessels [1]. In addition, PAUs occur exclusively in patients with extensive atherosclerotic plaque.

Figure 12.11â•… Contrast-enhanced computed tomography angiography in a patient with pene-trating atherosclerotic ulcer (open arrows) that has formed at a location of calcified (arrowhead) and noncalcified (closed arrow) plaque.

The PAU may contain itself or may progress to aortic dissection or rupture [55]. If the ulcer extends through the adventitia, a pseudoaneurysm can form. Stable patients presenting with PAU are treated medically with frequent clinical and radiological reassessment. Differentiation of the True and False Lumina The true and false lumina can usually be distinguished because of the differences in flow through the 2 channels. The true lumen is often smaller in caliber and has rapid antegrade flow. Imaging throughout the cardiac cycle can reveal rapid systolic expansion of the true lumen followed by compression and potentially complete collapse during diastole, which can compromise blood flow to end organs (Figure 12.12). The false lumen tends to be larger with slower flow than the true lumen. As a result, the false lumen will have delayed enhancement compared to the true lumen on dynamic contrast enhanced imaging studies. Flow within the false lumen may be retrograde or completely absent if there is complete thrombosis of the false lumen [56–58].

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F ig u r e 1 2 . 1 2 â•…Transversal spoiled gradient echo sequence images reveal movement of the intimal flap within the cardiac cycle in a patient with

Stanford type B aortic dissection (arrows). The true lumen is compressed during diastole (left image) and open during systole (right image).

In addition, it is important to note the presence of partial thrombosis of the false lumen, because this has recently been found to be associated with a higher risk of postdischarge mortality, relative to a completely patent false lumen, in patients with Stanford type B aortic dissections [19]. Localization of Communications Between the Two Lumina Localization of the entry tear (Figure 12.8) is essential in guiding therapeutic intervention, because the dissection can be effectively treated by occluding the entry site of the false lumen. After successful occlusion of the entry tear, with a covered stent graft for example, the false lumen of the dissection rapidly decompresses. Reentry tears in the intima, which allow communication between the true and false lumina, are important in allowing equalization of pressures between the 2 channels. These tears, or fenestrations, usually occur at the origins of branch vessels, created by tearing of the intima around the ostia of branch vessels. In such vessels, the integrity of the intima is maintained, although the vessel is then supplied by the false lumen. The equalization of pressures between the true and false lumina prevents complete collapse of the true lumen. In fact, one of the percutaneous treatment options for patients with aortic dissection is to create additional fenestrations in the intimal flap using an intravascular needle. This creates a direct communication between the true and false lumen, decompressing the false lumen and relieving the obstruction of the true lumen. Assessment of Branch Vessel Involvement Extension of the aortic dissection into branch vessels can result in various forms of cardiac, neurological, and visceral ischemia. Although extension of an ascending aortic

dissection into the aortic arch does not affect the need for operative management [35], knowledge of arch involvement could affect the type of surgery performed. In addition, arch involvement places patients at a higher risk of neurological deficits, particularly when the dissection extends into the cervical vessels (Figure 12.13). Identification of coronary artery involvement is important because it can lead to myocardial infarction. Differentiation of coronary artery stenosis due to extension of aortic dissection from atherosclerotic plaque is critical because the management is very distinct [10]. Branch involvement in the abdomen (Figure 12.8) can lead to multiorgan failure, which is a common cause of death in patients with aortic dissection [37]. Compromised perfusion of the side branches, as result of dissection, can happen when the intimal flap propagates into the branch artery, causing a stenosis in the vessel lumen. Alternatively, ischemia can occur as a result of branch vessel occlusion by the overlying intimal flap or when the true lumen completely collapses during diastole from increased pressure within the false lumen [10]. Signs of end-organ ischemia include (a) splenic or renal infarctions when the splenic and renal arteries are involved, respectively; (b) bowel wall thickening, pneumatosis, and/or pneumoperitoneum when the mesenteric arteries are involved; and (c) lower extremity ischemia when the dissection extends into the peripheral arteries. Measurement of Aorta Size Although absolute aortic size is a risk factor for developing an aortic dissection, many, if not most, aortic dissections occur in patients with aortic diameters less than 5.5 cm [59], the diameter traditionally used to decide when to repair ascending aorta aneurysms. The most important

2 0 0 Multimodality Imaging in Cardiovascular Medicine

F ig u r e 1 2 . 1 3 â•… Contrast-enhanced computed tomography angiography of the thoracic, abdominal, and pelvic vasculature (A) demonstrates extension of dissection in a patient with Stanford type A aortic dissection. The dissection extends cranially into the left common carotid artery (open arrow). The smaller and more anterior true lumen (solid arrows) feeds the celiac trunk, the superior mesenteric artery, and right renal artery (ostia not shown). The left renal artery is supplied by the false lumen (asterisk). The dissection extends into both common iliac arteries distally (arrowheads). Volume rendered reformats are also useful for demonstrating the extent of the dissection (B).

factor associated with aortic rupture is maximal crosssectional aorta diameter. The risk of rupture increases dramatically when the aortic diameter is $60 mm [60]. This is felt to be related to the law of La Place, which states that the stress within the wall of a cylinder is directly proportional to (a) the radius and (b) the pressure of the fluid within the cylinder and (c) inversely proportional to the wall thickness. Accurate determination of aorta size is important not only in the acute setting but also during follow-up evaluation. The most accurate and reproducible means of determining aortic cross-sectional diameters is off double-oblique multiplanar reformatted images [61]. Aortic Insufficiency Aortic insufficiency, or regurgitation, is a complication commonly seen in Stanford type A aortic dissections. Ascending aortic dissections can cause dilatation of the ascending aorta, which then causes enlargement of the aortic root. This prevents complete coaptation of the aortic valve leaflets during diastole, leading to aortic regurgitation. Alternatively, if the ascending aortic dissection extends into the aortic root, a leaflet of the aortic valve can become detached, leading to prolapse of the aortic valve leaflet. Finally, in severe ascending aortic dissections, where there is an extensive intimal tear, the intimal flap itself may prolapse through the aortic valve, preventing complete coaptation of the aortic valve leaflets (Figure 12.14A and B). Therefore, patients

with ascending aortic dissections are routinely evaluated with echocardiography to detect aortic regurgitation [62]. Aortic regurgitation can also be visualized using cine MRI sequences or cardiac-gated CT angiography (Figure 12.14C and D). The presence of aortic regurgitation is an indication for immediate aortic valve repair. Aortic Rupture Rupture of the adventitial layer of the aortic wall usually results in severe and potentially fatal complications. Rupture of the thoracic aorta leads to rapid exsanguination into the mediastinum, pleura, and/or pericardium, whereas rupture of the abdominal aorta results in retroperitoneal hemorrhage. In the thoracic aorta, these complications are accurately detected by MRI, CT, and echocardiography. For abdominal aortic rupture, CT and MRI are more accurate than ultrasonography (US). Signs of aortic rupture indicate a need for emergent repair, with mortality rates exceeding 50% [63]. Pericardial effusion in the setting of an aortic dissection should raise a high degree of suspicion of hemopericardium. This is most frequently recognized as hyperattenuating pericardial fluid with CT (Figure 12.15). When the descending thoracic aorta ruptures, blood typically exsanguinates into the left hemithorax resulting in a left hemothorax. Nonhemorrhagic pleural (Figure 12.16) and pericardial effusions are common and are often signs of impending rupture [64].

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F ig u r e 1 2 . 1 4 â•… (A and B) Intraoperative transesophageal echocardiogram in a patient with Stanford type A aortic dissection displays regurgitation of the intimal flap through the aortic valve during diastole (arrow in A). During systole, the intimal flap (solid arrows in B) can be seen within the aortic root and proximal ascending aorta (open arrows in B). Cardiac-gated contrast-enhanced computed tomography angiography images reconstructed during diastole (C) and systole (D) reveal the same findings.

jâ•… DIAGNOSIS Multiple diagnostic tests play an important role in evaluating and treating patients with AAS. These include electrocardiography (ECG), chest x-ray (CXR) radiography, US, transthoracic/transesophageal echocardiography (TTE/ TEE), computed tomography angiography (CTA), magnetic resonance angiography (MRA), and catheter angiography (CA). The roles and important features of these studies are discussed in the following paragraphs. Because the consequences of not treating an aortic dissection can be life threatening, the imaging test used to determine the diagnosis must have a high sensitivity and high negative predictive value. In a large meta-analysis [65] of TEE, CT, and MRI studies evaluating the diagnostic accuracy of the modalities for diagnosing aortic dissections, CT was the most accurate modality with a sensitivity of 100% and specificities of 92% to 100%. In addition to its very high degree of accuracy, CT can be performed very rapidly and safely in an emergency department setting. As a result, CTA is the diagnostic imaging

modality of choice for the rapid diagnosis of this potentially life-threatening disease. Electrocardiography ECG is usually the initial step for the rapid assessment of patients with an acute thoracic cardiovascular emergency. ECG can often differentiate between cardiac (ie, myocardial infarction) and noncardiac causes of acute chest pain (ie, aortic dissection, IMH, and PAUs). The ECG is normal in approximately 30% of patients with acute aortic dissection [16]. Occasionally, myocardial infarction and aortic dissection can occur simultaneously, such as when the dissection extends into the coronary arteries. This often results in ECG signs of acute myocardial infarction or acute ischemia [66]. These signs include ST-segment or T-wave abnormalities or left ventricular hypertrophy [11]. Patients with these ECG signs who are suspected of acute aortic disease must undergo further examinations before thrombolytic therapy can be administered to avoid potentially fatal consequences.

2 0 2 Multimodality Imaging in Cardiovascular Medicine

F ig u r e 1 2 . 1 5 â•…Precontrast (upper row) and contrast-enhanced (lower row) computed tomography images in a patient with Marfan syndrome and

Stanford type A aortic dissection reveal high-attenuation pericardial fluid (asterisks), consistent with hemopericardium and indicative of aortic rupture. Pulsation artifacts are present and compromise assessment of the aortic root on these noncardiac-gated CT images (arrow).

F ig u r e 1 2 . 1 6 â•… Bilateral pleural effusions (asterisks) are present in a patient with a Stanford type A aortic dissection (arrows). (A) Coronal and

transversal (B) balanced steady-state free precession MR images.

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Chest Radiography Patients with AAS also frequently have a CXR performed as part of the initial evaluation because it is performed rapidly and is inexpensive (Figure 12.5). Although CXR is useful for detecting secondary signs or complications of aortic dissection, it has a relatively low sensitivity and specificity for diagnosing aortic dissection [67,68]. The specificity (75%) and sensitivity (67%–81%) of CXR for aortic dissection are too low to confirm or exclude the presence of dissection. Furthermore, up to 10% to 20% of patients have normal chest radiographs [16,67–69]. The radiographic features most predictive of aortic dissection include enlargement of the aortic arch or aortic contour, widening of the mediastinum, and a tortuous aorta [67–70]. Widening of the mediastinum in patients with aortic dissection is due to mediastinal hemorrhage, but it can also be seen in many other conditions, such as mediastinal fat, lymphadenopathy, or neoplasm [70]. Pleural effusions, most commonly on the left, and displacement of intimal calcifications from the outer aortic shadow are also helpful predictors but are less frequent and nonspecific [67]. Because of the low accuracy of CXR for diagnosing aortic dissection, patients with a high index of suspicion should undergo additional imaging evaluation [71].

Echocardiography TTE and TEE have proven efficacy in evaluating patients with thoracic aortic dissections and are advantageous in

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emergency situations where time constraints and patient instability are primary concerns. TTE provides a rapid, noninvasive, readily available, and portable technique that can effectively assess secondary effects of dissection. It can identify aortic valve complications, aortic insufficiency, regional wall-motion abnormalities, and pericardial effusion [72]. TTE is effective in visualizing the aortic root and aortic arch but is limited in imaging the distal ascending aorta and descending aorta because of the small acoustic window that a physician must use, having to avoid the rib cage and lungs in order to image the aorta effectively [73]. Because of the low sensitivity for diagnosing descending aorta pathology, a normal TTE should not preclude additional imaging evaluation. TEE provides a much better view of the thoracic aorta than TTE but is more invasive and more expensive. TEE can be used to identify intimal tears, intimal calcification displacement, and flow characteristics of the true and false lumen (Figure 12.17). Color-flow Doppler TEE is effective in detecting aortic insufficiency (Figure 12.14A and B). In addition, it can identify other abnormalities that may Â�provide valuable prognostic information such as cardiac tamponade, cardiac wall-motion abnormalities, valvular disease, IMH, and PAU [72,74,75]. As a result, TEE is often performed in the operating room to assist the cardiac surgeons operating on patients with Stanford type A aortic dissection. The sensitivities and specificities of TEE for the diagnosis of thoracic aortic dissections have been reported to be 86% to 100% and 75% to 100%, respectively [65,76].

F ig u r e 1 2 . 1 7 â•… Intraoperative transesophageal echocardiography demonstrates high flow in the true lumen (asterisk), whereas no flow is detected in the false lumen (arrow).

2 0 4 Multimodality Imaging in Cardiovascular Medicine

However, TEE also has its own limitations because it is unable to image the entire aorta with a blind spot in the distal ascending aorta and proximal aortic arch created by interference by the air-filled trachea and left main stem bronchus [76]. Multiplanar TEE in combination with TTE can minimize this effect but cannot fully eliminate the problem. TEE can also have difficulties visualizing the aortic arch branch vessels, the mid and distal abdominal aorta, and in the thoracic aorta in individuals with esophageal and/or aortic tortuosity [76]. Other limitations of echocardiography include the fact that these modalities are observer dependent, which can be problematic for follow-up examinations [77], and TEE is an invasive procedure often requiring sedation [73]. Computed Tomography Because of its universal availability and very high diagnostic accuracy, CT angiography using modern, multidetector CT (MDCT) scanners has become the gold standard for evaluating patients with AAS in the emergency setting. With 64-slice and greater MDCT scanners, it is now possible to evaluate, in a single examination, the thoracic aorta, pulmonary arteries, and coronary arteries in patients presenting with chest pain [78]. Acute IMH will appear as a crescentic area of aortic wall thickening that is hyperattenuating relative to the normal aortic wall on noncontrast enhanced CT images, and which does enhance following the administration of IV contrast (Figure 12.2). An intimal flap is absent in patients with IMH. PAUs are easily recognized with CT (Figure 12.11) because of the ease of identifying calcified and noncalcified plaque at the site of ulceration. The diagnosis of an aortic dissection with CT is based on the identification of an intimal flap, separating the true and false lumina. CTA for diagnosing aortic dissection is reported to have a sensitivity of 100% and specificity of 98% to100% [65]. With cardiac-gated, ECG-triggered CTA, it is now possible to acquire images of the ascending aorta that minimize the effects of cardiac motion. Because it is not possible to distinguish between Stanford type A and Stanford type B dissections clinically, CTA should routinely be performed with ECG triggering to avoid motion artifact in the ascending aorta [79], at least for the initial study used to ascertain the presence and extent of a dissection. For follow-up of descending aorta dissections, CTA without cardiac gating is sufficient. The role of CTA in the workup of patients with AAS is to determine if an aortic dissection is present, its location and extent, branch-vessel involvement, and any complications associated with the aortic dissection. With MDCT scanners, it is possible to acquire images with isotropic Â�spatial resolution. Computer workstations with image postprocessing software can then be used to generate multiplanar, reformatted, and volume-rendered images of the vasculature to assist in the visualization of the aortic dissection (Figure 12.13).

When ECG triggering is used to acquire images, it is possible to reconstruct images at different phases of the cardiac cycle to identify aortic regurgitation as well (Figure 12.14C and D). Limitations of CT include the use of ionizing radiation and nephrotoxic contrast material. However, the relative risk of radiation, particularly in an older patient, and the risk of contrast-induced nephropathy (CIN) from iodinated contrast are negligible compared to the risks associated with AAS in a patient with a high pretest probability of AAS. In patients with a lower pretest probability of an aortic dissection or in patients being evaluated in follow-up, MRI is a very reasonable alternative. CTA also has a very important role in following patients after initial presentation. This includes detection of complications after operative repair of ascending aortic dissections, growth in aortic size, change in dissection extent, and end-organ ischemia. Magnetic Resonance Imaging Patients with AAS can be accurately evaluated with MRA. IMH will appear as a crescentic mural thickening on MRI. The signal intensity of the hematoma will vary depending on the age and type of hemoglobin present. In the acute setting, the IMH will be hypointense on T1-weighted sequences and hyperintense on T2-weighted sequences. In the subacute setting, the IMH will be hyperintense on T1-weighted sequences as well. To distinguish the increased signal in the aortic wall due to hemorrhage from the adjacent periaortic fat, fat-suppressed dark-blood sequences should be used. PAU can be accurately assessed with MRI and MRA techniques. MRI and MRA will reveal a focal ulceration in the aortic wall with a variable degree of surrounding intramural hemorrhage. The role of MRA in patients with aortic dissections includes determining the location and extent, distinguishing between the true and false lumen, and assessing branch vessel involvement. The sensitivities and specificities of MRA for diagnosing aortic dissection have been reported to be 91% to 100% and 94% to 100%, respectively [65]. The diagnosis of a dissection is made when an intimal flap can be visualized between the true and false lumen. Because the appearance of an intimal flap varies considerably, it is important to review the raw data and MPR images in addition to MIP images. Differences in flow through the true and false lumina can be assessed with time-resolved CE-MRA (Figure 12.4) or phase contrast sequences. The false lumen will enhance later than the true lumen because of slower flow than that of the true lumen. Often, the entry and exit points of the dissection can be visualized with MRA. In patients who cannot receive Â�gadolinium-based contrast materials, noncontrast enhanced MRA methods, including traditional T1 spinecho, T1-weighted double inversion recover, T2-weighted and steady state free precession (SSFP) sequences, are

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F ig u r e 1 2 . 1 8 â•…Transversal T1-weighted magnetic resonance imaging reveals high signal intensity of the thrombosed false lumen on precontrast

images (A) and low signal intensity on postcontrast images (B) of a Stanford type B dissection.

highly effective (Figures 12.3B, 12.10, and 12.16). Using a single-shot SSFP technique, it is possible to diagnose aortic dissection with very high accuracy without any contrast material [80]. MRA has also been shown to be highly accurate in following patients for complications after surgical or endovascular therapy as well. MRA is often preferred over CTA in patients who are likely to have frequent followup examinations, such as young adults, and in patients with renal insufficiency because MRA does not use ionizing radiation or require the use of nephrotoxic contrast material. Complications of aortic dissection that can be seen with MRI/MRA include extension of the dissection proximally or distally, true lumen collapse, false lumen thrombosis (Figure 12.18), or pseudoaneurysm. Accurate measurements of luminal diameters on follow-up MRAs are necessary to detect anastamotic stenosis before it becomes symptomatic and to determine the risk of rupture if the dissection continues to grow. Catheter Angiography CA (Figures 12.19 and 12.20) through percutaneous retrograde arterial catheterization had been considered the gold standard of imaging aortic dissection for many years [81,82]. However, the development of cross-sectional imaging has demonstrated that the accuracy of conventional aortography is less than once thought, and cross-sectional imaging has replaced aortography as the first-line imaging modality in patients with suspected AAS. The sensitivity and specificity of CA for the diagnosis of aortic dissection are 88% and 95%, respectively [10]. Aortography has a relatively high rate of false-negative studies because of occasional

F ig u r e 1 2 . 1 9 â•…Digital subtraction angiography of the aorta (aortography) in a patient with abdominal aortic dissection. The true lumen gives rise to the right renal artery. The left renal artery arises from the false lumen and is not readily displayed on this image.

inadequate opacification of the false lumen. Incomplete visualization of the false lumen can also occur when the catheter tip is placed distal to the primary tear and the false lumen is not opacified [10,76,83]. Aortography has several other disadvantages in respect to diagnosing aortic dissection. To accurately visualize aortic dissection through aortography, iodinated contrast material, which is potentially nephrotoxic, is usually used

2 0 6 Multimodality Imaging in Cardiovascular Medicine

the work-up should begin with CXR followed by crosssectional imaging. In the vast majority of patients, CTA with ECG gating should be the imaging study of choice. MRA is a very good alternative for patients in whom iodine contrast material and ionizing radiation are undesirable. For follow-up imaging in patients with aortic dissection, echocardiography, CTA, and MRA all have important roles to be considered.

jâ•…Refe rences

Figure 12.20â•…Digital subtraction angiography of the aorta (aortography)

in a patient with focal aortic dissection with a small intimal flap (arrow).

and injected at different levels and Â�multiple projections to define the anatomy of the aorta and extent of the aortic dissection. CA is also invasive and uses ionizing radiation. Important features of aortic dissection cannot be accurately visualized and defined, such as wall thickness, vessel size, and extraluminal complications. In addition, the cost and time required to perform an aortography are considerably greater than those for cross-sectional imaging. Although the use of CA has become limited in the initial diagnosis of patients with suspected AAS, it remains a very useful technique for the endovascular management of some patients with these conditions, primarily as a means of creating fenestrations in the intimal flap to create communications between the true and false lumen [84,85] and for the placement of endovascular stent grafts [47–49,86,87]. jâ•… CONCL USIO N Appropriate evaluation and management of patients with suspected AAS require a comprehensive approach that includes several diagnostic imaging studies. Patients presenting with suspected AAS should initially be evaluated with vital signs, ECG, and blood tests to distinguish between cardiac and noncardiac causes of chest pain. In patients who do not have a myocardial infarction, the work-up should then be based on the stability of the patient. In unstable, hypotensive patients suspected of AAS, the initial evaluation should be done with echocardiography with anticipation of emergent surgical intervention. In stable patients,

1. Cooke JP, Kazmier FJ, Orszulak TA. The penetrating aortic ulcer: pathologic manifestations, diagnosis, and management. Mayo Clin Proc. 1988;63(7):718–725. 2. Evangelista A, Mukherjee D, Mehta RH, et al. Acute intramural hematoma of the aorta: a mystery in evolution. Circulation. 2005;111(8):1063–1170. 3. Golledge J, Eagle KA. Acute aortic dissection. Lancet. 2008;372(9632):55–66. 4. Hayashi H, Matsuoka Y, Sakamoto I, et al. Penetrating atherosclerotic ulcer of the aorta: imaging features and disease concept. Radiographics. 2000;20(4):995–1005. 5. Macura KJ, Corl FM, Fishman EK, Bluemke DA. Pathogenesis in acute aortic syndromes: aortic dissection, intramural hematoma, and penetrating atherosclerotic aortic ulcer. AJR Am J Roentgenol. 2003;181(2):309–316. 6. Movsowitz HD, Lampert C, Jacobs LE, Kotler MN. Penetrating atherosclerotic aortic ulcers. Am Heart J. 1994;128(6 Pt 1):1210–1217. 7. O’Gara PT, DeSanctis RW. Acute aortic dissection and its variants: toward a common diagnostic and therapeutic approach. Circulation. 1995;92(6):1376–1378. 8. Sundt TM. Intramural hematoma and penetrating atherosclerotic ulcer of the aorta. Ann Thorac Surg. 2007;83(2):S835–S841. 9. Vilacosta I, Roman JA. Acute aortic syndrome. Heart. 2001;85(4): 365–368. 10. Erbel R, Alfonso F, Boileau C, et al. Diagnosis and management of aortic dissection. Eur Heart J. 2001;22(18):1642–1681. 11. Hagan PG, Nienaber CA, Isselbacher EM, et al. The International Registry of Acute Aortic Dissection (IRAD): new insights into an old disease. JAMA. 2000;283(7):897–903. 12. Mohr-Kahaly S, Erbel R, Kearney P, Puth M, Meyer J. Aortic intramural hemorrhage visualized by transesophageal echocardiography: findings and prognostic implications. J Am Coll Cardiol. 1994;23(3):658–664. 13. Ganaha F, Miller DC, Sugimoto K, et al. Prognosis of aortic intramural hematoma with and without penetrating atherosclerotic ulcer: a clinical and radiological analysis. Circulation. 2002;106(3):342–348. 14. Meszaros I, Morocz J, Szlavi J, et al. Epidemiology and clinicopathology of aortic dissection. Chest. 2000;117(5):1271–1278. 15. Clouse WD, Hallett JW Jr, Schaff HV, et al. Acute aortic dissection: population-based incidence compared with degenerative aortic aneurysm rupture. Mayo Clin Proc. 2004;79(2):176–180. 16. Collins JS, Evangelista A, Nienaber CA, et al. Differences in clinical presentation, management, and outcomes of acute type a aortic dissection in patients with and without previous cardiac surgery. Circulation. 2004;110(11 suppl 1):II237–II242. 17. Suzuki T, Mehta RH, Ince H, et al. Clinical profiles and outcomes of acute type B aortic dissection in the current era: lessons from the International Registry of Aortic Dissection (IRAD). Circulation. 2003;108(suppl 1):II312–II317. 18. Mukherjee D, Evangelista A, Nienaber CA, et al. Implications of periaortic hematoma in patients with acute aortic dissection (from the International Registry of Acute Aortic Dissection). Am J Cardiol. 2005;96(12):1734–1738.

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19. Tsai TT, Evangelista A, Nienaber CA, et al. Partial thrombosis of the false lumen in patients with acute type B aortic dissection. N Engl J Med. 2007;357(4):349–359. 20. Januzzi JL, Marayati F, Mehta RH, et al. Comparison of aortic dissection in patients with and without Marfan’s syndrome (results from the International Registry of Aortic Dissection). Am J Cardiol. 2004;94(3):400–402. 21. Januzzi JL, Isselbacher EM, Fattori R, et al. Characterizing the young patient with aortic dissection: results from the International Registry of Aortic Dissection (IRAD). J Am Coll Cardiol. 2004;43(4):665–669. 22. Williams GM, Gott VL, Brawley RK, Schauble JF, Labs JD. Aortic disease associated with pregnancy. J Vasc Surg. 1988;8(4):470–475. 23.â•‡ Eagle KA, Isselbacher EM, DeSanctis RW. Cocaine-related aortic dissection in perspective. Circulation. 2002;105(13):1529–1530. 24. Cavanzo FJ, Taylor HB. Effect of pregnancy on the human aorta and its relationship to dissecting aneurysms. Am J Obstet Gynecol. 1969;105(4):567–568. 25. Judge DP, Dietz HC. Marfan’s syndrome. Lancet. 2005;366(9501): 1965–1976. 26. Bonderman D, Gharehbaghi-Schnell E, Wollenek G, Maurer G, Baumgartner H, Lang IM. Mechanisms underlying aortic dilatation in congenital aortic valve malformation. Circulation. 1999;99(16):2138–2143. 27. Dorsa FB, Tunick PA, Culliford A, Kronzon I. Pseudoaneurysm of the thoracic aorta due to cardiopulmonary resuscitation: diagnosis by transesophageal echocardiography. Am Heart J. 1992;123(5):1398–1400. 28. Moles VP, Chappuis F, Simonet F, et al. Aortic dissection as complication of percutaneous transluminal coronary angioplasty. Cathet Cardiovasc Diagn. 1992;26(1):8–11. 29. Pieters FA, Widdershoven JW, Gerardy AC, Geskes G, Cheriex EC, Wellens HJ. Risk of aortic dissection after aortic valve replacement. Am J Cardiol. 1993;72(14):1043–1047. 30. Tiessen IM, Roach MR. Factors in the initiation and propagation of aortic dissections in human autopsy aortas. J Biomech Eng. 1993;115(1):123–125. 31. Wilson SK, Hutchins GM. Aortic dissecting aneurysms: Â�causative Â�factors in 204 subjects. Arch Pathol Lab Med. 1982;106(4): 175–180. 32. Mehta RH, O’Gara PT, Bossone E, et al. Acute type A aortic dissection in the elderly: clinical characteristics, management, and outcomes in the current era. J Am Coll Cardiol. 2002;40(4):685–692. 33. Mehta RH, Bossone E, Evangelista A, et al. Acute type B aortic dissection in elderly patients: clinical features, outcomes, and simple risk stratification rule. Ann Thorac Surg. 2004;77(5):1622–1628. 34. Daily PO, Trueblood HW, Stinson EB, Wuerflein RD, Shumway NE. Management of acute aortic dissections. Ann Thorac Surg. 1970;10(3):237–247. 35. DeBakey ME, McCollum CH, Crawford ES, et al. Dissection and dissecting aneurysms of the aorta: twenty-year follow-up of five hundred twenty-seven patients treated surgically. Surgery. 1982;92(6):1118–1134. 36. Svensson LG, Labib SB, Eisenhauer AC, Butterly JR. Intimal tear without hematoma: an important variant of aortic dissection that can elude current imaging techniques. Circulation. 1999;99(10):1331–1336. 37. Crawford ES, Svensson LG, Coselli JS, Safi HJ, Hess KR. Surgical treatment of aneurysm and/or dissection of the ascending aorta, transverse aortic arch, and ascending aorta and transverse aortic arch: factors influencing survival in 717 patients. J Thorac Cardiovasc Surg. 1989;98(5 Pt 1):659–673. 38. Glower DD, Speier RH, White WD, Smith LR, Rankin JS, Wolfe WG. Management and long-term outcome of aortic dissection. Ann Surg. 1991;214(1):31–41. 39. Trimarchi S, Nienaber CA, Rampoldi V, et al. Contemporary results of surgery in acute type A aortic dissection: the International Registry of Acute Aortic Dissection experience. J Thorac Cardiovasc Surg. 2005;129(1):112–122.

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40. Takeshita S, Sakamoto S, Kitada S, Akutsu K, Hashimoto H. Angiotensin-converting enzyme inhibitors reduce long-term aortic events in patients with acute type B aortic dissection. Circ J. 2008;72(11):1758–1761. 41. Tefera G, Acher CW, Hoch JR, Mell M, Turnipseed WD. Effectiveness of intensive medical therapy in type B aortic dissection: a single-center experience. J Vasc Surg. 2007;45(6):1114–1118. 42. Elefteriades JA, Lovoulos CJ, Coady MA, Tellides G, Kopf GS, Rizzo JA. Management of descending aortic dissection. Ann Thorac Surg. 1999;67(6):2002–2005. 43. Kodama K, Nishigami K, Sakamoto T, et al. Tight heart rate control reduces secondary adverse events in patients with type B acute aortic dissection. Circulation. 2008;118(suppl 14):S167–S170. 44. Winnerkvist A, Lockowandt U, Rasmussen E, Radegran K. A prospective study of medically treated acute type B aortic dissection. Eur J Vasc Endovasc Surg. 2006;32(4):349–355. 45. Williams GM. Treatment of chronic expanding dissecting aneurysms of the descending thoracic and upper abdominal aorta by extended aortotomy, removal of the dissected intima, and closure. J Vasc Surg. 1993;18(3):441–448. 46. Trimarchi S, Nienaber CA, Rampoldi V, et al. Role and results of surgery in acute type B aortic dissection: insights from the International Registry of Acute Aortic Dissection (IRAD). Circulation. 2006;114(suppl 1):I357–I364. 47. Nathanson DR, Rodriguez-Lopez JA, Ramaiah VG, et al. Endoluminal stent-graft stabilization for thoracic aortic dissection. J Endovasc Ther. 2005;12(3):354–359. 48. Grabenwoger M, Fleck T, Czerny M, et al. Endovascular stent graft placement in patients with acute thoracic aortic syndromes. Eur J Cardiothorac Surg. 2003;23(5):788–793. 49. Eggebrecht H, Lonn L, Herold U, et al. Endovascular stent-graft placement for complications of acute type B aortic dissection. Curr Opin Cardiol. 2005;20(6):477–483. 50. Czerny M, Zimpfer D, Rodler S, et al. Endovascular stentgraft placement of aneurysms involving the descending aorta originating from chronic type B dissections. Ann Thorac Surg. 2007;83(5):1635–1639. 51. Brown KE, Eskandari MK, Matsumura JS, Rodriguez H, Morasch MD. Short and midterm results with minimally invasive endovascular repair of acute and chronic thoracic aortic pathology. J Vasc Surg. 2008;47(4):714–722. 52. Kapustin AJ, Litt HI. Diagnostic imaging for aortic dissection. Semin Thorac Cardiovasc Surg. 2005;17(3):214–223. 53. Robbins RC, McManus RP, Mitchell RS, et al. Management of patients with intramural hematoma of the thoracic aorta. Circulation. 1993;88(5 Pt 2):II1–II10. 54. Kazerooni EA, Bree RL, Williams DM. Penetrating atherosclerotic ulcers of the descending thoracic aorta: evaluation with CT and Â�distinction from aortic dissection. Radiology. 1992;183(3):759–765. 55. Stanson AW, Kazmier FJ, Hollier LH, et al. Penetrating atherosclerotic ulcers of the thoracic aorta: natural history and clinicopathologic correlations. Ann Vasc Surg. 1986;1(1):15–23. 56. Mohr-Kahaly S, Erbel R, Rennollet H, et al. Ambulatory follow-up of aortic dissection by transesophageal two-dimensional and colorcoded Doppler echocardiography. Circulation. 1989;80(1):24–33. 57. Sommer T, Fehske W, Holzknecht N, et al. Aortic dissection: a comparative study of diagnosis with spiral CT, multiplanar transesophageal echocardiography, and MR imaging. Radiology. 1996;199(2):347–352. 58. Yamada T, Tada S, Harada J. Aortic dissection without intimal rupture: diagnosis with MR imaging and CT. Radiology. 1988;168(2):347–352. 59. Pape LA, Tsai TT, Isselbacher EM, et al. Aortic diameter . or 5 5.5 cm is not a good predictor of type A aortic dissection: observations from the International Registry of Acute Aortic Dissection (IRAD). Circulation. 2007;116(10):1120–1127. 60. Sueyoshi E, Sakamoto I, Hayashi K, Yamaguchi T, Imada T. Growth rate of aortic diameter in patients with type B aortic dissection during the chronic phase. Circulation. 2004;110(11 suppl 1):II256–II261.

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61. Bireley WR 2nd, Diniz LO, Groves EM, Dill K, Carroll TJ, Carr JC. Orthogonal measurement of thoracic aorta luminal diameter using ECG-gated high-resolution contrast-enhanced MR angiography. J Magn Reson Imaging. 2007;26(6):1480–1485. 62. Epperlein S, Mohr-Kahaly S, Erbel R, Kearney P, Meyer J. Aorta and aortic valve morphologies predisposing to aortic dissection: an in vivo assessment with transoesophageal echocardiography. Eur Heart J. 1994;15(11):1520–1527. 63. Erbel R, Oelert H, Meyer J, et al. Effect of medical and surgical therapy on aortic dissection evaluated by transesophageal echocardiography. Implications for prognosis and therapy. The European Cooperative Study Group on Echocardiography. Circulation. 1993;87(5):1604–1615. 64. Flachskampf FA, Daniel WG. Aortic dissection. Cardiol Clin. 2000;18(4):807–817. 65. Shiga T, Wajima Z, Apfel CC, Inoue T, Ohe Y. Diagnostic accuracy of transesophageal echocardiography, helical computed tomography, and magnetic resonance imaging for suspected thoracic aortic dissection: systematic review and meta-analysis. Arch Intern Med. 2006;166(13):1350–1356. 66. Kamp TJ, Goldschmidt-Clermont PJ, Brinker JA, Resar JR. Myocardial infarction, aortic dissection, and thrombolytic therapy. Am Heart J. 1994;128(6 Pt 1):1234–1237. 67. Jagannath AS, Sos TA, Lockhart SH, Saddekni S, Sniderman KW. Aortic dissection: a statistical analysis of the usefulness of plain chest radiographic findings. AJR Am J Roentgenol. 1986;147(6):1123–1126. 68. von Kodolitsch Y, Nienaber CA, Dieckmann C, et al. Chest radiography for the diagnosis of acute aortic syndrome. Am J Med. 2004;116(2):73–77. 69. Miller WT. Thoracic aortic aneurysms: plain film findings. Semin Roentgenol. 2001;36(4):288–294. 70. Petasnick JP. Radiologic evaluation of aortic dissection. Radiology. 1991;180(2):297–305. 71. Hartnell GG, Wakeley CJ, Tottle A, Papouchado M, Wilde RP. Limitations of chest radiography in discriminating between aortic dissection and myocardial infarction: implications for thrombolysis. J Thorac Imaging. 1993;8(2):152–155. 72. Armstrong WF, Bach DS, Carey LM, Froehlich J, Lowell M, Kazerooni EA. Clinical and echocardiographic findings in patients with Â�suspected acute aortic dissection. Am Heart J. 1998;136(6): 1051–1060. 73. Scott CH, Keane MG, Ferrari VA. Echocardiographic evaluation of the thoracic aorta. Semin Roentgenol. 2001;36(4):325–333. 74. Chan KL. Usefulness of transesophageal echocardiography in the diagnosis of conditions mimicking aortic dissection. Am Heart J. 1991;122(2):495–504.

75. Bossone E, Evangelista A, Isselbacher E, et al. Prognostic role of transesophageal echocardiography in acute type A aortic dissection. Am Heart J. 2007;153(6):1013–1020. 76. Bansal RC, Chandrasekaran K, Ayala K, Smith DC. Frequency and explanation of false negative diagnosis of aortic dissection by Â�aortography and transesophageal echocardiography. J Am Coll Cardiol. 1995;25(6):1393–1401. 77. Shiga T, Wajima Z, Inoue T, Ogawa R. Survey of observer variation in transesophageal echocardiography: comparison of anesthesiology and cardiology literature. J Cardiothorac Vasc Anesth. 2003;17(4):430–442. 78. Vrachliotis TG, Bis KG, Haidary A, et al. Atypical chest pain: coronary, aortic, and pulmonary vasculature enhancement at biphasic single-injection 64-section CT angiography. Radiology. 2007;243(2):368–376. 79. Posniak HV, Olson MC, Demos TC. Aortic motion artifact simulating dissection on CT scans: elimination with reconstructive segmented images. AJR Am J Roentgenol. 1993;161(3):557–558. 80. Pereles FS, McCarthy RM, Baskaran V, et al. Thoracic aortic dissection and aneurysm: evaluation with nonenhanced true FISP MR angiography in less than 4 minutes. Radiology. 2002;223(1): 270–274. 81. Guthaner DF, Miller DC. Digital subtraction angiography of aortic dissection. AJR Am J Roentgenol. 1983;141(1):157–161. 82. Shuford WH, Sybers RG, Weens HS. Problems in the aortographic diagnosis of dissecting aneuryms of the aorta. N Engl J Med. 1969;280(5):225–231. 83. Cigarroa JE, Isselbacher EM, DeSanctis RW, Eagle KA. Diagnostic imaging in the evaluation of suspected aortic dissection. Old standards and new directions. N Engl J Med. 1993;328(1):35–43. 84. Hartnell GG, Gates J. Aortic fenestration: a why, when, and how-to guide. Radiographics. 2005;25(1):175–189. 85. Williams DM, Brothers TE, Messina LM. Relief of mesenteric ischemia in type III aortic dissection with percutaneous fenestration of the aortic septum. Radiology. 1990;174(2):450–452. 86. Flecher E, Cluzel P, Bonnet N, et al. Endovascular treatment of descending aortic dissection (type B): short- and medium-term results. Arch Cardiovasc Dis. 2008;101(2):94–99. 87. Nienaber CA, Fattori R, Lund G, et al. Nonsurgical reconstruction of thoracic aortic dissection by stent-graft placement. N Engl J Med. 1999;340(20):1539–1545.

13

Claudication

aL i Z. merCH anT Ge orgeTa mi H a i anUrag S a HU Sa njaY Rajag oPaL a n

Claudication is the most common presenting symptom of patients with peripheral arterial disease (PAD) [1]. It is estimated that as many as 10 million people in the United States have PAD [2]. Advanced age, smoking, and diabetes have the strongest association with PAD, ensuring a continued increased incidence in the United States [3]. This predicted increase will place greater demand on health care services across the country. It is clear that awareness about the diagnosis and treatment of PAD is becoming increasingly important, as PAD can serve as a marker for systemic atherosclerotic or inflammatory disease [4,5]. Although loss of limb function or amputation is a high risk in advanced stages [6], it is overshadowed by the increased risk of mortality from myocardial infarction and stroke [7]. The aim of this chapter is to familiarize the reader with 3 major modalities of noninvasive assessment of PAD, including ultrasound, computed tomography angiography (CTA), and magnetic resonance angiography (MRA). Each method has its advantages and disadvantages and they are discussed in detail. In addition, explanations are given on examination procedures and the level of detail to be expected from each study. Having a fundamental knowledge of each method will allow proper selection and help to minimize delay in making an accurate decision regarding treatment approach.

jâ•…C LINICAL PRESENTATION OF LOWER EXTREMITY ARTERIAL DISEASE PAD is mainly caused by atherosclerotic disease of the arteries, 90% of which occurs in the lower extremities [8]. Other causes include embolization, inflammatory processes, congenital anomalies, and entrapment syndromes. Atherosclerotic plaque eventually leads to luminal stenosis and results in

poor tissue perfusion, causing claudication. Ischemic claudication, described as pain, heaviness, or numbness in the muscles induced with walking and relieved with rest, is the most frequent presenting symptom. However, clinicians who solely rely on the classic history of claudication to detect PAD are likely to miss 85% to 90% of cases [9]. With progression in PAD, rest pain and evidence of chronic tissue hypoperfusion such as ischemic ulceration and Â�gangrene can develop, which may not be seen in early stages. Acute limb ischemia has a more typical clinical presentation constituted by the 5Ps (pallor, pain, paresthesias, Â�pulselessness, and paralysis). In these cases, the acuity of presentation may help determine which imaging modality is chosen, knowing that patients presenting with advanced limb ischemia (eg, sensory changes, paralysis) warrant immediate intervention. Initial evaluation of a patient with suspected PAD should include a history and physical exam. This can help define the etiology and may also direct what type of detailed imaging is selected. An ankle-brachial index (ABI) has a high sensitivity and specificity (90% and 98%, respectively), and is a simple, noninvasive test used to evaluate the presence of PAD (ABI ,0.9) [10,11]. Additionally, segmental limb pressures and waveform analysis can help to further localize the disease. In a number of patients who are either asymptomatic or have mild symptoms, aggressive medical therapy and risk factor modification without further diagnostic studies may be all that is necessary. In patients with lifestyle-modifying symptoms, where an intervention may be indicated, a more detailed evaluation of the vasculature is warranted. CTA and MRA angiography are clearly the leading modalities to delineate the lower extremity circulation in light of their ease of acquisition, spatial coverage, and identification of concomitant stenosis/disease of the abdominal aorta and visceral branches. Table 13.1 outlines common indications of MRA and CTA of the abdominal, pelvic, and lower extremity vessels in individuals presenting with lower extremity symptoms. Duplex ultrasonography has a rather limited role in the comprehensive assessment of lower extremity circulation with the exception of targeted follow-up of limited anatomic segments (eg, the common femoral/superficial femoral artery [SFA]) or graft segments that are accessible to imaging [12,13]. 209

210 210 Multimodality Imaging in Cardiovascular Medicine

jâ•… Table 13.1â•… Indications for magnetic resonance Â�angiography or computed tomography angiography of the lower extremity Atherosclerotic peripheral arterial disease (claudication and critical limb ischemia) Postintervention follow-up (grafts and stentsa) Arteritis and inflammatory disorders • Buerger’s diseasea • Giant-cell arteritis • Systemic lupus erythematosis • Pseudoxanthoma elasticum, Ehlers-Danlos syndrome • Takayasu’s arteritis Embolization • Proximal aneurysm (abdominal/femoral/popliteal) • Left ventricular thrombusb • Ulcerated atherosclerotic plaques Dissection Congenital • Arteriovenous malformationsb • Hypoplasia and acquired coarctation of the abdominal aorta (mid-aortic syndrome) Miscellaneous • Fibrodysplasia (external iliac artery, renal arteries) • Persistent sciatic artery • Popliteal etiologies (adventitial cystic disease, entrapment: arterial or venousb) a

Computed tomography angiography preferred modality. Magnetic resonance angiography preferred modality.

b

jâ•… ANATOMIC CONSIDERATIONS Figure 13.1 illustrates the normal anatomy of the lower extremity vessels. Typically, the anatomical area of interest in patients presenting with lower extremity symptoms includes evaluation from the abdominal aorta down to the distal vessels. Iliac and Femoral Arteries The distal abdominal aorta bifurcates into the left and right common iliac arteries. The internal iliac artery supplies the organs of the pelvis, while the external iliac artery continues as the common femoral artery below the level of the inguinal ligament. The common femoral artery bifurcates into the SFA and the profunda femoris (deep femoral). The profunda normally supplies the thigh musculature, yet becomes an important source of collaterals to the lower extremity in the event of occlusion of the SFA. Popliteal Trifurcation The distal SFA continues toward the knee and at this point is known as the popliteal artery. Below the knee, at the level of the popliteus muscle, there are 2 major branches. The medial branch is the tibioperoneal trunk, which bifurcates into the common peroneal and the posterior tibial branch. The lateral branch is known as the anterior tibial artery. In a small number of cases, there are variations to this branching pattern, but they have little clinical significance except for revascularization purposes.

F i g u re 1 3 . 1 â•…Normal 3-station magnetic resonance angiography showing the maximal intensity projection of the abdomen/pelvis, thigh, and lower leg stations. The images and level of detail are typical for the quality available on current scanners.

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Distal Vessels Usually, the anterior and posterior tibial arteries are the dominant vessels supplying the foot. The anterior tibial and posterior tibial may be absent or terminate early in 4% to 12% and 1% to 5% of cases, respectively [5]. The peroneal, although subject to much anatomical variation, is an important source of collateral circulation. It ends by giving rise to the anterior and posterior perforating branches, approximately 5 cm above the ankle. The posterior tibial ends by dividing into the lateral and medial plantar branches, while the anterior tibial ends by dividing into the arcuate and the deep plantar branches. The distal branches of the anterior and posterior tibial arteries join in the foot to form the plantar arch vessels.

jâ•…M AG NETIC RESONANCE AN G IOGRAPHY MRA has emerged over the last decade as a preferred modality in imaging of PAD. Although earlier techniques had significant limitations, modern scanners and software allow for rapid and robust contrast-enhanced (CE) MRA imaging from the abdominal aorta to the proximal pedal vessels. The goal of this section is to provide the reader with a simple, stepwise approach to high-quality MR imaging of the lower extremity arteries. The acquisition protocols and their physics will be discussed only as they relate to practical issues. The selection of sequences used in peripheral MRA is based on their ability to fulfill a specific imaging purpose. Although there are standardized protocols comprising certain sequences, each study can be tailored toward an individual patient’s symptoms or a clinician’s question about a certain diagnosis. MR sequences are a compromise between resolution and time required for acquisition. A runoff study is performed with multiple coils of coverage called stations. Generally, the resolution and the slice thickness will vary such that the lower leg station is performed with the highest resolution and the thinnest slices. However, resolution must be balanced against time so that the arterial structures are acquired before venous filling contaminates the image. Venous filling may particularly be a problem in patients with advanced disease (especially patients with critical limb ischemia) and can vary with age and cardiac output. The table movement between stations should allow for overlap of the imaged anatomy so that there are no gaps in coverage. This may particularly be a problem in the common femoral segments and an overlap of at least 5 to 10 cm must be built into the protocol. Parallel imaging (IPAT/SENSE/ASSET) is almost always used for imaging the lower extremities. It is a technique that accelerates the acquisition of data over the expansive field of view (FOV) required for imaging the abdominal, pelvic, and lower extremity vessels. The time saved with parallel imaging (typically by half) allows for improved resolution. The cost of this improvement relative

211

to the nonaccelerated technique results in a decrease in signal-to-noise ratio (SNR) as described by the equation below, where x is the acceleration factor: SNR =

1 x

Usually an acceleration factor of at least 2 is used (30% decrease in SNR), although higher factors of up to 4 (50% decrease in SNR) may be used in the abdomen/pelvis station. Since the aorta and pelvic vessels are larger and have more contrast, they generate a higher absolute signal, so image quality is still maintained despite a greater decrease in SNR. Pulse Sequences in MRA of the Lower Extremities

Localization Sequences Localizers are low-resolution images that allow a global overview of the anatomy of the abdomen and lower extremities and facilitate easy identification of vascular structures. Steady-state free precession (SSFP) sequences allow Â�bright-blood imaging of the vascular system and usually suffice for vessel localization. Occasionally, dark-blood sequences can be obtained to improve vessel conspicuity.

Time-Resolved MRA This is a commonly used sequence based on a gradient echo approach that is typically performed before 3-dimensional (3D) MRA acquisition. This technique relies on a number of features that improve temporal resolution and signal characteristics at the expense of spatial resolution. The approach involves acquisition of a complete 3D data set prior to arrival of contrast. Subsequently, the center of k-space is replenished with each acquisition, whereas peripheral k-space lines are replenished periodically (echo sharing). In conjunction with parallel imaging, one may achieve superior temporal resolution of 200 to 300 milliseconds per slice (partition). Multiple sequential acquisitions are obtained during administration of a small amount of contrast (3–5 cc). All the acquisitions are viewed as a movie loop, which provides dynamic arterial imaging. This allows visualization of discrepant flow, for example, if 1 leg is more severely diseased than the other and can also provide gross anatomic information. Time-resolved angiography has numerous vendor-specific acronyms such as time-resolved intravascular contrast kinetics (TRICKSTM). Figure 13.2A and B depicts typical images obtained using this technique. Table 13.2 lists an example of typical parameters used for a lower extremity angiography.

3D Gradient Echo Angiographic Sequences The CE, 3D angiographic data set is acquired using a heavily T1-weighted spoiled gradient echo sequence obtained in

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F i g u re 1 3 . 2 â•…Time-resolved magnetic resonance angiography: A, Early image from cine loop prior to complete arrival of contrast. B, Improved visualization as contrast transits through the lower extremity vessels. With permission from Ref. 5.

the coronal plane, and repeated at every imaging station as the contrast travels through the arteries (3D Turbo FLASH or SPGR). The intra-arterial contrast shortens the T1 time, which allows for visualization of the vessel. Spoiling is used to destroy any residual transverse magnetization and to accentuate the T1 weighting. These sequences can be performed with fat saturation in the abdomen/pelvis and upper leg stations, although this results in increased imaging time and decreased SNR.

as the volumetric interpolated breath-hold examination (VIBETM) imaging or inversion recovery (IR)-prepared gradient echo sequences as IR-FLASH or IR-SSFP. VIBE allows for improved signal from the background tissue structures. These sequences can be added to the standard protocol with only a minimal increase in total scan time and are usually obtained in the infrarenal aorta, inguinal region, and popliteal fossa. This can help to screen for aneurysms that could be missed on luminographic images alone by allowing improved characterization of the vessel wall.

Postcontrast Sequences Additional imaging to characterize the vessel wall may often be desired postcontrast, particularly in the abdomen, to better delineate the interface between thrombus, atheroma, and lumen. Sequences for this purpose include a fat-saturated volumetric T1 gradient echo sequence such

Protocol Considerations

Patient Preparation and Scan Setup Patients should be told that the table will move intermittently during the exam and to remain completely

jâ•… Table 13.2â•… Acquisition parameter for 3-dimensional contrast-enhanced magnetic resonance angiography Abdomen/Pelvis Slice thickness (mm)

1.4

Thigh 1.4

Calf

Time Resolved

1.2

1.3

Number of slices

88

80

104

60

Field of view (mm)

500 3 375

500 3 400

500 3 400

500 3 400

Matrix (lines)

384 3 245

512 3 291

512 3 291

448 3 186

Spatial resolution (mm)

1.4 3 1.3 3 1.4

1.4 3 1.0 3 1.4

1.4 3 1.0 3 1.2

1.9 3 1.1 3 1.3

Averages

1

1

1

1

Acceleration factor

2

2

2

2

Bandwidth (Hz/pixel)

500

360

360

470

Scan duration (sec)

15

21

26

8.5

k-Space acquisition

Linear

Centric

Centric

Centric

c h A p t e r 13

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still while in the scanner. This prepping can reduce the patient’s anxiety and improve compliance. The patient is usually placed on the scanner table in a leg-first, supine position with a 20-gauge antecubital IV (22-guage may also be acceptable given the low rate of contrast infusion). Compressive devices are typically placed in the lower thigh/popliteal fossa to help minimize venous contamination. An appropriately configured foam pad compressing the popliteal fossa is often sufficient and is an improvement over blood pressure cuffs placed in the lower thigh that were typically inflated to venous compression pressures (≈50 mm Hg).

Scanning Localizer images are obtained followed by high-resolution noncontrast mask images of all 3 stations. CE angiography is initiated either following a timing bolus or using MR fluoroscopic triggering. A breath-holding spell during the abdomen/pelvis station can reduce motion artifact. The table is then moved such that the upper (thigh) and lower leg stations are sequentially acquired. A repeat acquisition at the lower leg level may be performed to ensure adequate imaging with arterial contrast present. Precontrast and postcontrast images are subtracted from each other to remove signal from surrounding tissue.

Field of View For any given scanner, the FOV should be increased in order to obtain the maximum anatomic coverage and to minimize the number of table movements required to encompass the desired anatomy. The slab thickness is a product of the number of slices and the slice thickness and must be large enough to cover the vessels of interest. The slab positions, especially in the thigh and the lower leg stations, are slightly tilted anteriorly and posteriorly, respectively, to ensure coverage of the common femoral artery and the popliteal artery. A rough rule of thumb is to ensure that the slab nearly touches the skin surface at the groin and popliteal fossa as the common femoral and popliteal artery run very superficially in these locations (Figure 13.3).

Contrast Timing Timing is critically important in multistation MRA and the following 2 principles must be kept in mind: 1. The acquisition of the central lines of k-space must be synchronized with a stable level of full-contrast opacifcation in the arterial system. 2. The acquisitions need to be completed before venous filling occurs, particularly at the lower leg level. Two techniques can be used to synchronize image acquisition with the arterial phase of contrast passage, a timing bolus, or a triggered bolus technique.

Appropriate angulation of multistation 3-dimensional slabs necessary for high-resolution magnetic resonance angiography acquisition in order to avoid cutoff of pertinent vascular structures.

FIguRE 13.3

A timing bolus acquisition consists of a series of T1-weighted images taken sequentially every second through the vessel of interest. The acquisition is initiated simultaneously with the injection of a small amount of contrast (≈2 cc) and a saline flush. The image with maximal opacification can be determined visually or quantitatively by imaging a region of interest (ROI), typically the abdominal aorta, slightly above the level of the renals. The appropriate time delay for initiation of the scan from the time of contrast injection is then calculated using the formula [5] (assuming linear ordering of k-space data):  Tin j   Tsc  Scan delay = Tcirc +  +  scan  ,  ° ° 2  2  where T circ is the amount of time in seconds it takes for contrast to arrive at the ROI, Tinj is the duration of time to administer the contrast, and Tscan is the acquisition time of the sequence. The scan delay allows the midway point of the arterial phase of the contrast injection and the midway point of the image acquisition to coincide. To minimize truncation artifacts, it is desirable to have contrast present at a relatively stable level throughout the scan. The timing above refers to the first station that typically uses a linear k-space filling scheme. The thigh and lower leg stations typically use a centric filling scheme as it is assumed that the vessels in these stations are maximally filled when imaging begins in these stations. With a triggered bolus technique, the contrast is injected as intended for the scan, and multiple monitoring images of the vessel of interest are obtained and displayed in real time on the scanner console. Scan triggering is then usually performed based on the visualization of arterial contrast. Bolus triggering can also be performed using a user-specific attainment of signal intensity threshold, following which the technician acquires a high-resolution MRA. The main

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F i g u re 1 3 . 4 â•… (A) Thoracic and abdominal aortic maximal intensity projections (MIPs) show mild atherosclerosis in the descending thoracic aorta with a large-sized infrarenal abdominal aortic aneurysm. Note that the upper arrow is in an area of large thrombus that may be missed but is clearly visible in the following volumetric interpolated breath-hold examination images. (B) Coronal MIP of the abdominal station demonstrates poor contrast opacification of the aortic aneurysm due to late acquisition of the high-resolution sequence.

advantage of the bolus triggering technique is the ease of use; most technologists feel very comfortable initiating the scan at the point of contrast arrival. Also, the real-time nature of the scan initiation accounts for any variation in the patient’s cardiac output. An advantage of the timing bolus technique is that the scan will start at the plateau phase of the contrast with no time lost switching from scan monitoring to image acquisition. Figure 13.4A and B shows differences in image quality affected by proper and missed timing.

Contrast Administration A biphasic contrast bolus is ideal to prolong the arterial opacification phase and to minimize venous filling. The initial rate should be 1.2 to 1.5 cc/s for the first half of the bolus, followed by 0.6 to 0.8 cc/s for the second half. For combined imaging of the abdomen, pelvis, and lower extremities, typically 35 to 40 cc of contrast is administered. This drawn-out injection scheme allows for a prolonged plateau phase, longer acquisition times, and minimal venous contamination. The latter complication can range from being a nuisance to rendering an interpretation nearly impossible. There are several methods to minimize venous contamination: 1. Complete image acquisition within 40 to 50 seconds, although venous circulation times can be variable

depending on age and cardiac output. Keep in mind that critical limb ischemia and cellulitis may increase likelihood of venous contamination and shorter acquisition times may be Â�necessary [14]. 2. Use a biphasic administration of contrast as described above. 3. Use compressive devices to delay venous filling (as previously described). This technique should be used with caution in patients with bypass grafts, as they are often superficial in location and may be compressed. Alternate Imaging Strategies Another strategy that can be employed to avoid venous contamination is to acquire lower leg images first followed by the abdomen/pelvis and thighs in the standard fashion. Two separate boluses of contrast are used for the separate acquisitions. This technique was found to yield diagnostic images free of venous overlay in 95% of studies [15] and has demonstrated good agreement with selective digital subtraction angiography (DSA) [16]. Other groups have reported similar findings, with a significant improvement in diagnostic accuracy at the calf level compared to standard bolus-chase methods [15,17]. If imaging of the venous structures is desired, the sequence can be run in reverse order (legs → thighs → abdomen) after the arterial acquisition, with a 30-second pause in between.

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Noncontrast Angiographic Techniques The most commonly used noncontrast MRI technique is time-of-flight (TOF) imaging [18–20]. This 2D or 3D technique uses a gradient echo sequence with short repetition time that exploits the signal differences between the unsaturated spins of the inflowing blood and presaturated spins of the stationary tissue. In addition to the extensive anatomical coverage needed in peripheral MR angiography (which makes TOF impractical), another limiting aspect of this sequence is the saturation of protons in vessels within the imaging slab especially in 3D slabs. Nevertheless, in clinical practice 2D TOF is still used for evaluation of lower extremity vasculature and has been shown to be as accurate as conventional angiography when depicting luminal stenosis [21–23]. The association of Gd-based contrast agents used in CE MRA studies with nephrogenic systemic fibrosis (NSF) in patients with severe renal insufficiency [24,25] has increased the clinical need for noncontrast MRA techniques. Table 13.3 lists a set of sequences based on the glomerular filtration rate (GFR) that may prohibit the use of Gd contrast. The majority of these nonenhanced MR angiograms are based on the method developed by Miyazaki et al [26]. This technique relies on acquiring 2 electrocardiogram (ECG)-gated 3D partial Fourier fast spin echo (FSE) sets of images, one triggered on systolic and one on diastolic cardiac cycle. An ECG preparation scan provides an appropriate ECG triggering time for each of the 2 acquisitions. Bright-blood MR angiography is achieved by subtracting systolic from diastolic images and shows promise in visualizing peripheral vessel stenosis. However, this method’s diagnostic confidence is limited due to artifacts mostly from inadequate triggering delays [27–29]. Our institution’s experience with noncontrast MRA technique has focused on using a recently developed fatsuppressed dark-blood 3D FSE acquisition (SPACETM sequence [30]), based on the method developed by Mugler et al [31,32]. By using variable refocusing flip angles, it allows longer echo train duration and has nonselective refocusing pulses that minimize echo spacing. These modifications significantly increase its efficiency over conventional 3D FSE. Additionally, flowing blood is dephased and blood signal suppressed without the need for double inversion preparation, allowing the use of thick 3D slabs and efficient coverage of large vascular territories. In a recent 2-station study that involved comparing sameresolution 1-mm3 acquisitions of 3D CE MRA and noncontrast 3D T1-weighted SPACE in PAD patients and normal subjects, we found excellent correlation of localized luminal area quantification between the 2 techniques [33]. This suggests that luminal stenosis evaluation with this technique is possible and reliable, similarly to CE MRA, except that 3D-SPACE precludes the use of maximum intensity projection (MIP) reconstruction. While significantly longer acquisition

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jâ•… Table 13.3â•… Peripheral arterial disease protocols based on renal function No contraindications to Gd (GFR .30 mL/min) • Localizers • Time-resolved angiography • 3-Dimensional magnetic resonance angiography • Volumetric interpolated breath-hold examination or comparable postcontrast T1 images (abdominal aorta and popliteal arteries) Contraindications to Gd (GFR ,30 mL/min) • Localizers • Time-resolved angiography of distal vessels (3–4 cc of Gd) • 3-Dimensional-SPACE or other noncontrast techniques

time (between 25–30 min) is spent for the coverage of both abdominal aorta and SFA regions, with 3D-SPACE, this is well justified by this sequence’s superior ability to assess vessel wall remodeling and stenosis severity [33] (Figure 13.5). The only practical limitation of 3D-SPACE is its inability to assess infrapopliteal circulation for which true submillimeter resolution is required. However, based on our present experience, we propose a new approach to image lower extremity arteries using only a minimal dose of Gd contrast in people in whom NSF is a concern. Specifically, the abdomen/pelvis and thigh stations could be covered by 3D-SPACE acquisitions and a time-resolved sequence could be used to image the infrapopliteal circulation. We believe this may provide a clinically relevant hybrid option for angiographic imaging of the lower extremities. Moreover, it is expected that the spatial resolution achieved currently with 3D-SPACE can be significantly improved with peripheral coils with additional elements; this may ultimately allow expansion of coverage to the infrapopliteal territory. A novel angiographic MR imaging technique is that of global coherent free precession imaging. In this technique, spins passing through a preselected ROI acquire signal, while the background is suppressed, resulting in an angiographic appearance. The slab can be positioned freely, resulting in dynamic image acquisitions. This manipulation can be performed in real time from the scanner console. Potential clinical applications include realtime evaluation of guidance of interventional procedures. Postprocessing and Image Interpretation MIP images can be created to ease in visualization of a thicker volume of data. However, the thin-slice multiplanar reconstruction (MPR) images must always be reviewed to avoid misinterpretation from artifacts. Modern workstations can also create images using volume rendering (VR) technique, as well as endoscopic views of the images. Although these images are visually appealing, they have a tendency to be inaccurate.

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F i g u re 1 3 . 5 â•…T1-weighted SPACE (dashed border, A and B) and contrast-enhanced (CE) magnetic resonance angiography (MRA) (solid border,

A and B) images of abdominal aorta (A) and superficial femoral artery (SFA) (B) segments showing lumen narrowing and plaque deposition in a 64-year-old peripheral arterial disease patient with right iliac bypass (arrowheads show area of total occlusion). Observe that the SFA segment (B) shows a normal-looking lumen (as CE MRA depicts) with vessel wall remodeling that is only obviously depicted in T1-weighted SPACE images (white arrows).

Clinical Applications MRA has been well validated for the detection and quantification of stenoses and occlusions in patients with atherosclerotic PAD [34–36]. Initial studies using 2D TOF imaging demonstrated a high level of agreement with conventional angiography in the iliofemoral region but poorer correlation below the knee [37]. Multiple recent studies have demonstrated that CE MRA performed with a bolus-chase moving-table technique has a sensitivity and specificity greater than 95% when compared with catheter angiography [38–40]. Further, several studies have demonstrated better detection of below-knee vessels in patients with critical limb ischemia with MRA compared to x-ray DSA [41–43]. Although there is slight tendency for MRA to overestimate the severity of stenosis, there is a high level of agreement with DSA and it is a well-accepted modality for intervention planning [39,44]. Some studies have demonstrated a resultant change in management based on detection of patent vessels [45]. The sections below provide details on MRA in various PAD entities.

the status of collateral vessels (see Figure 13.6). The length of occlusion and the level at which the native circulation is reconstituted is quite important, as this will determine the feasibility of percutaneous or surgical approaches. Evaluation of the proximal vessels goes beyond just assessing for luminal irregularities and severity of stenosis. The

Atherosclerotic PAD Claudication or ischemia-related symptoms secondary to atherosclerosis is the most common indication for MRA of the lower extremity circulation. Since imaging is usually performed prior to either surgical or percutaneous revascularization, emphasis will be placed on findings relevant to planned interventions. Given the multisegmental nature of atherosclerotic disease, a stepwise approach with initial assessment of proximal vessels (aorta, iliac, common femoral disease) followed by the thigh and distal vessels is helpful. The study should demonstrate which vessels are patent, severity of disease, anatomic extent of stenosis or occlusion, if location and sites of anastomosis if grafts are present, and

F i g u re 1 3 . 6 â•…Right iliac occlusion: coronal maximal intensity projec-

tion illustrating complete occlusion of the right common iliac artery (single arrow) with faint infrarenal aortic collaterals (dashed arrows) to the distal right common iliac artery.

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jâ•… Table 13.4â•… Steps for 3-dimensional contrast-enhanced magnetic resonance angiography with time-resolved angiography â•‡ 1. Patient placed on table feet-first and centered at mid abdomen â•‡ 2. Abdomen steady-state free precession 3 plane scout (20 s) â•‡ 3. Upper leg 3 plane scout (20 s) â•‡ 4. Lower leg 3 plane scout (20 s) â•‡ 5. Time-resolved angiography with 4–5 cc of contrast (≈10 s) â•‡ 6. 3-Dimensional angio noncontrast acquisition at abdomen (15 s) â•‡ 7. 3-Dimensional angio noncontrast acquisition at thighs (21 s) â•‡ 8. 3-Dimensional angio noncontrast acquisition at lower legs (15 s) â•‡ 9. Timing or triggered bolus scan (coronal plane centered on aorta) 10. Contrast injected (half at 1.4 cc/s, then other half at 0.7 cc/s, followed by flush) 11. 3-Dimensional contrast angio of abdomen/pelvis (in-line subtraction from precontrast mask) 12. 3-Dimensional contrast angio of thigh (21 s) 13. 3-Dimensional contrast angio of lower leg 3 2 (26 s each) 14. Volumetric interpolated breath-hold examination postcontrast sequences at abdomen, femorals, and popliteals Note: For venous studies following arterial studies, simply re-run the sequence in reverse order—wait approximately 30 seconds and reacquire the lower leg, the upper leg, and then the abdomen/pelvis.

degree of tortuosity, wall thickness, areas of ulceration, localized dissection, and thrombus can all be assessed on a good-quality study (Table 13.4 describes a step-by-step guide to completing a routine lower extremity MRA). Aorta-Iliac Disease.â•… High-grade occlusive disease of the terminal aorta or proximal iliac arteries can be seen in Leriche syndrome, a clinical entity characterized by the triad of diminished or absent femoral pulses, gluteal or thigh claudication, and impotence in males. Pallor and wasting of the lower extremities may also be seen in extreme cases. Distal disease involving the femoral and tibioperoneal circulation may frequently coexist.

status of the popliteal artery, the tibioperoneal trunk, and the vessels of the lower leg is crucial to determine whether revascularization or amputation may be necessary in the presence of rest pain (Figure 13.8). Imaging of the pedal vessels may be required, although they may not be adequately imaged on the standard multistation exam. A dedicated high-resolution stationary exam of the pedal circulation performed at a separate time is often a good Â�strategy. Alternately, this could be done as a dedicated leg station followed by a conventional 3-station MRA approach.

Postintervention Evaluation Graft Surveillance.â•… Although ultrasound imaging is commonly used for graft surveillance, MR imaging can Â�provide

SFA Disease.â•… Occlusive disease of the SFA is often surprisingly symmetric. High-grade occlusions often result in claudication of the calf musculature, and if accompanied by severe runoff disease, may progress to rest pain (Figure 13.7). Analysis of MR angiographic images in this circumstance requires attention to the length of the diseased segment and the level of reconstitution of flow, as this can determine whether surgical or percutaneous treatment is pursued. The level of resumption of a normal vessel caliber and its extent is quite important as it determines what type of graft is used when surgical revascularization is chosen. Distal (tibioperoneal) Disease.â•… Patients with infra-articular distal (runoff) disease can present with critical limb ischemia (rest pain and/or lower extremity ulceration) with diabetics being particularly at risk. Early venous filling and arteriovenous shunting are common in patients with severe runoff disease and can cause difficulty in image interpretation. If patients have known lower extremity ulcers, steps should be taken to shorten pelvic and thigh image acquisition time to minimize venous contamination in the legs. Knowing the

F i g u re 1 3 . 7 â•‡ Severe and diffuse multisegment atherosclerotic disease of the bilateral superficial femoral arteries. There are multiple areas of near-total occlusion.

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F i g u re 1 3 . 8 â•…Time-resolved magnetic resonance angiography shows 1 vessel runoff in the left leg. The left anterior tibial and peroneal arteries have greater than 90% lesions (dual arrows). The right peroneal artery is abruptly occluded above the level of the ankle. The right peroneal artery has at least moderate atherosclerosis prior to the level of the occlusion (Â�single arrow). There are faint collaterals present. With permission from Ref. 5.

detailed anatomy when a stenosis is suspected [46]. Grafts can be revised or salvaged if the disease is identified and treated early [47]. Aortobifemoral grafts are commonly used for the treatment of long-segment iliac artery occlusions. Anastomotic complications, such as pseudoaneurysm formation, can be well visualized. Multiplanar visualization allows for improved evaluation of the graft and the anastomotic sites. Although synthetic graft materials do not present a problem for MR imaging, surgical clips at the site of the anastomosis can produce artifact, inhibiting proper evaluation. Rotation and examination from multiple angles can unmask an area of stenosis. Stents.â•… Endovascular stents, frequently placed in the iliac and femoral vessels, are often used to increase the longterm patency of percutaneous interventions. The composition of the stent determines the amount of artifact produced. Stainless steel stents result in significant signal dropout, sometimes precluding luminal visualization, and misleading one to think there is an occlusion (Figure 13.9). Nitinol-containing stents usually produce minimal artifact. If there is question about occlusion versus artifact, a plain radiograph can be reviewed. If not available, other clues such as a sharply marginated border and the absence of collaterals can confirm the presence of stent rather than a true occlusion. Review of thin-section MPR from the unsubtracted source images will often allow depiction of the stent artifact. Current versions of aortic endovascular stent grafts produce minimal, if any, artifact. MRA is well studied in evaluation of patients status-post covered stent

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F i g u re 1 3 . 9 â•…Thick maximal intensity projection images from a patient with bilateral iliac artery stents. Care must be taken in evaluating these images as it can be misinterpreted as severe stenosis. With permission from Ref. 5.

graft repair of abdominal aortic aneurysms [48] and has been found to be superior to computed tomography (CT) and DSA for the detection of endoleak [49–51]. VIBE imaging sequence can provide excellent lumen depiction with minimal artifact and can be quite useful for this purpose.

Buerger’s Disease Buerger’s disease, also known as thromboangiitis obliterans, is a disorder that predominantly affects young male smokers. It causes an obliterative arteritis of the small and medium vessels of the upper and lower extremities [52]. The characteristic angiographic hallmark is the presence of extensive distal occlusive disease accompanied by the development of collaterals. A distinguishing feature from common atherosclerotic disease is the relative preservation of the proximal vessels [53].

Embolic Disease Arterial emboli of the lower extremity circulation usually present with acute ischemia. The origin is frequently from the heart or proximal aortic atheroma or thrombus [54]. The emboli typically lodge in the peripheral vessels or at areas of stenosis, where they are prevented from travelling distally. The degree of ischemia depends on the number of preexisting collaterals. If an MRA is ordered, it must be done urgently to aid percutaneous or surgical intervention. Figure 13.10 demonstrates the presence of a popliteal clot in a patient who presented with left lower leg ischemia. The proximal aorta should be evaluated as the source of the embolus in all cases. A cardiac MR may be carried out with delayed-enhancement imaging to evaluate for an intracardiac source(s).

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F i g u re 1 3 . 1 0 â•… (A) High-resolution angiography shows multiple aneurysmal segments in the distal right superficial femoral artery (white arrows). Also note the significant stenosis proximal to the aneurysmal segment (proximal to first arrow). (B) Axial volumetric interpolated breath-hold examination more clearly demonstrates the thrombus present in a right popliteal artery aneurysm (dual arrows).

Aneurysms and Dissection Atherosclerotic aneurysms predominantly involve the infrarenal abdominal aorta (Figure 13.11 shows 2 infrarenal saccular aneurysms), although they can be seen in the vessels of the pelvic and lower extremity circulation. A segment can be labeled an aneurysm if it exceeds the reference vessel diameter by 150% to 200% [55]. Abdominal aneurysms (Figure 13.4A and B) are often associated with femoral and popliteal aneurysms; therefore, if an abdominal aneurysm is found, detailed evaluation of the distal vessels is essential [56]. This evaluation should include review of the source images and additional complementary sequences (eg, VIBE) to assess for vessel wall pathology (Figure 13.12A and B). Aneurysms in more distal sites such as the iliac, femorals, and popliteals (70% of distal aneurysms being popliteal) [57] are more prone to complications including rupture, thrombosis, and embolization [58]. Spontaneous abdominal and/or iliac dissection is less common than propagation of a proximal dissection. Figure 13.13 demonstrates the appearance of an aortic dissection extending from the thoracic aorta into the iliac vessels. The origin of vessels with regard to true versus false lumen is an important piece of information obtained from an MR angiographic study of a dissection. Contributions of each lumen to the supply of the abdominal and pelvic vasculature are extremely important, in particular, disparate perfusion of the kidneys. When spontaneous aortic or iliac dissections do occur, there is often an underlying connective tissue abnormality present, such as Ehlers-Danlos syndrome or fibromuscular dysplasia [59,60]. Pseudoaneurysms occur most often due to prior trauma or may represent a complication of a surgical procedure [61].

F i g u re 1 3 . 1 1 â•… 3-Dimensional volume-rendered magnetic resonance

angiography of the abdominal aorta showing 2 saccular aneurysms (white arrows).

Inflammatory Arteritides MRA is an excellent technique for inflammatory largevessel arteritides as it provides a complete assessment of spatial extent of disease, vessel wall inflammation [62], and concomitant cardiac involvement. Takayasu’s arteritis is a classic indication for combined MRA and cardiac MR imaging to assess for aortic root and valve involvement. Giant-cell arteritis presents in older patients and classically

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to Takayasu’s, the patient’s age and the pattern of the diseased vessels will help differentiate the two. Arteriovenous Malformations and Fistulas.â•… Arteriovenous malformations (AVMs) are congenital anomalies that consist of abnormal connections between the arterial and venous structures, without an intervening capillary bed. As a result, AVMs cause an abnormal early opacification of venous structures (Figure 13.14A and B: AVM of the mid-portion of the left thigh). The abnormal early venous

F i g u re 1 3 . 1 2 â•… (A, B) Illustrate a large intramural hematoma clearly visible within the aneurysmal abdominal aorta (white arrows).

F i g u re 1 3 . 1 3 â•… 3-dimensional volume-rendered image showing an aortic dissection extending into the iliac arteries. Bilateral renal artery aneurysms are also noted. With permission from Ref. 5.

affects medium-sized arteries; it can involve the vessels of the aortic arch as well as the lower extremities [63,64]. Although giant-cell arteritis presents in a fashion similar

F i g u re 1 3 . 1 4 â•… (A) Significant venous contamination on the left leg

due to arteriovenous malformations. (B) High-resolution axial images of the legs show multiple superficial venous structures consistent with arteriovenous shunting.

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filling during the arterial phase of imaging identifies the AVM. Time-resolved imaging using a rapid frame rate may occasionally be helpful in such instances. Arteriovenous fistulas are usually traumatic or iatrogenic in origin, and are often seen in the femoral vessels following cardiac catheterization. Congenital Disorders and Entrapment Syndromes.â•… Uncommon causes of aortic narrowing include congenital abnormalities such as abdominal coarctation, Williams syndrome, and neurofibromatosis. In these disorders, an area of Â�constriction can be present in the mid-portion of the abdominal aorta, and is often associated with bilateral renal artery stenosis [65,66]. Klippel-Trenaunay and Parkes-Weber syndromes are conditions with abnormal arteriovenous connections and hemihypertrophy or hemiatrophy of the distal lower extremity. Angiographic imaging in these disorders reveals abnormalities of both the arterial supply and of the draining veins. Time-resolved angiography may help in identifying brisk arteriovenous communications as seen in the Parkes-Weber syndrome and assist in the differentiation from KlippelTrenaunay syndrome, which is usually associated with venous anomalies and consequent slow flow. Delayed imaging in the venous phase can be helpful in evaluation of such patients. Popliteal entrapment syndrome usually presents as claudication in young, otherwise healthy individuals (15:1 male predilection) [67]. It results from abnormal insertion of the medial head of the gastrocnemius muscle, causing compression of the popliteal artery in the popliteal fossa. If entrapment is clinically suspected, it is important to specify this when ordering the test. In these patients, provocative maneuvers, such as imaging during plantar flexion against resistance, can increase the sensitivity of diagnosis [68]. Time-resolved angiography can easily establish the diagnosis when performed in conjunction with provocative exercise. This may be followed by a high-resolution 3D CE angiogram at rest (without plantar flexion) to establish restoration of patency and additionally evaluating contiguous vascular beds. Finally, venous compression, which is fairly common in these patients, must be ruled out by performing a 2D-TOF sequence with an arterial saturation slab. Cystic adventitial disease is an uncommon disorder resulting in localized arterial narrowing that may progress to occlusion. It often involves the popliteal arteries and is characterized by the development of myxoid cystic changes of the adventitia, with resultant compression of the vessel lumen. Review of the axial source images is important in its recognition. Artifacts and Pitfalls Artifacts should always be considered in the differential diagnosis of a suspected MRA abnormality. Stent artifact is a potential cause of apparent localized vascular occlusion and can be recognized by reviewing source images, where

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metal will usually have a characteristic MR appearance from signal dropout. Indwelling metallic structures such as prosthetic joint replacements may also produce extensive artifact. Although the artifact can result in the appearance of an occlusion or missing vessel, they are usually easy to recognize. Artifacts may also result from poor timing of the arterial bolus. If triggering is performed too early, a ringing artifact also known as Gibbs or truncation artifact is frequently seen. In certain cases, this artifact can mimic a dissection. However, review of the source images and the characteristic appearance of this finding usually allow the correct assessment to be made. In some circumstances, repetition of the acquisition with improved timing may be necessary to delineate between true abnormalities versus artifact. Inappropriate positioning of the acquisition slab (3D volume) may result in exclusion of the vessel of interest from the images, resulting in apparent stenosis/occlusion. Review of the imaging slab position indicates that the vessels are actually not included in the image, explaining the abrupt cutoff. Image subtraction used in MRA demonstrably improves the contrast-to-noise ratio of the images, but mandates motion-free source images and identical patient positioning during the acquisition of the mask and CE images. Injection of undiluted contrast into veins can result in the appearance of a pseudostenosis. The presence of high concentrations of gadolinium due to the intrinsic slower flow rates in veins results in significant T2 shortening causing susceptibility artifact. This is usually problematic during upper extremity MRA near the subclavian artery region if the contrast is injected from the ipsilateral side. Contrast bolus rate, timing of acquisition, or site of administration of contrast may need to be altered to avoid this artifact.

jâ•… CT ANGIOG RAPHY The use of multidetector CT for vascular applications began with the introduction of 4-slice, 0.5-second temporal resolution CT scanners. Further advances in technology led to increases in z-axis coverage with a single rotation and better temporal resolution. This has allowed for rapid scanning times and achievement of submillimeter isotropic voxels. These incremental technical advances have led to establishing CT angiography as a viable modality in angiographic assessment of the lower extremities. Peripheral CTA is diffusely employed for the evaluation of patients with suspected disease of the lower extremity vessels. This modality is broadly available and allows the production of high-resolution images in very little time. The introduction of CTA for peripheral vessels imaging is relatively recent, although several studies published recently have been devoted to the evaluation of its diagnostic accuracy. When compared to invasive angiography, CTA revealed a good overall sensitivity and specificity (95% and 96%, respectively) in detecting more than 50%

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stenoses involving the peripheral arteries [69]. Generally, better results both in terms of accuracy and reproducibility have been reported in the evaluation of iliac and femoropopliteal arteries compared with the more distal territories. The use of faster scanners (16-slice and 64-slice) seems to provide a more homogeneous performance throughout the lower extremity arterial tree [69]. Protocol Considerations Most multidetector CT scanners available on the market today are capable of adequately assessing the distal vessels in lower extremities. In order to image vessels ,1 mm in diameter, which is typically the case in pedal vessels, submillimeter detector collimation is necessary. Patients are placed on the scanner table in a feet-first and supine orientation. The typical FOV extends from the lower thorax (diaphragm) to the toes with an average scan length of 110 to 130 cm. The scanning protocol for peripheral CTA begins with a scout image of the entire FOV followed by a test bolus or bolustriggering acquisition (based on the operator’s preference as described previously). This is followed by a CE angiographic acquisition during arterial contrast phase. A second late acquisition of the calf vessels is typically prescribed in the event of inadequate pedal opacification during the arterial phase. The duration of a typical CTA including patient setup should take no more than 15 minutes.

Acquisition Parameters The selection of the specific acquisition parameters depends on the employed scanner model as well as the patient’s body habitus. The 2 main adjustable parameters are the tube voltage and current. The voltage is typically set at 120 kilovolts (kV), although 100 kV provides acceptable images with significantly reduced radiation and can be employed in most individuals who are not obese [70]. Tube current is usually 200 to 300 milliamperes (mA) and again can be adjusted upward if the patient is very large. Breath-holding spell is requested only for the abdomen/pelvis section of the image acquisition in order to reduce motion artifact. In multidetector CT spiral scans, the volume coverage speed (v, cm/s) can be estimated by the following formula: v =

Mscoll p , t rot

where M  number of simultaneous acquired slices, scoll  collimated slice width, p  pitch, and trot  gantry rotation time. Although current-generation scanners offer improved spatial resolution, their increased detector size and rotation speeds pose the risk of out-running the bolus of contrast. Accordingly, adjustments in both the pitch and the gantry rotation speed must be made in order to achieve a table translation speed of no more than 30 mm/s. In a 64-slice scanner, this usually is achieved by a reduction in trot to 0.5 second and a decrease in pitch to 0.8.

Contrast Injection Intravenous contrast is given by using a power injector into an antecubital vein (20–22 gauge). As detailed in the MRA section, since contrast arrival time may vary, this may be ascertained using a small test bolus injection or using an automated bolus-triggered technique. Empirically, a contrast bolus length of at least 30 seconds should be used to be able to image all patients. When the bolus-chase technique is employed, 100 to 120 mL of contrast (with an iodine concentration between 320 and 370 mg/mL) is administered at a rate of 4 mL/s. When an automated bolus detection algorithm is used, the ROI is placed in the aorta immediately below the level of the diaphragm. A repetitive low-dose acquisition of the suprarenal abdominal aorta is started approximately 10 seconds after contrast injection begins. The actual peripheral angiographic acquisition is started when the contrast enhancement reaches a prespecified Hounsfield Unit threshold (eg, 110 HU). Although the use of higher iodine concentration (370–400 mg/mL) contrast agents yields improved enhancement, there is likely no difference in diagnostic ability [71]. Although it is possible to use lower iodine concentrations with equally good results [72], this generally requires higher flow rates (via 18-gauge vs. 20-gauge IV) to compensate.

Reconstruction Parameters and Image Interpretation With peripheral CTA, the modern scanners can easily yield well over a thousand high-resolution images per examination. Usually 2 data sets are reconstructed including thick and thin sets. The thick set (5.0 mm) is used for general assessment, whereas the thin set (0.6–0.75 mm) is more suited for detailed evaluation. A medium-to-soft [20–25] reconstruction kernel is generally applied for image reconstruction in peripheral CTA. The image formats most favored for the assessment of peripheral vessels are no different from other applications and include transverse source images, VR, shaded surface rendering, MIP, MPR, and curved planar reformation (CPR). VR images are a good way to get a 3D visualization of all the vessels and their relationship to the surrounding structures. By changing the window width and centering, the operator can exclude or subtract soft tissues. Although MIP images lack a 3D quality, they offer the ability to rapidly view large volumes of data. Care must be taken viewing MIP images when calcium is present, as it can overestimate the severity of stenotic lesions. For detailed evaluation, especially when calcium and stents are present, the raw MPR images should always be reviewed. A systematic approach should be instituted so that the information and format of a report is reproducible and comprehendible. Evaluation should begin with the proximal vessels and then proceed distally. Any areas of stenoses are described in terms of location, extension, and severity. Additional findings such as the presence of aneurysm, dissection, thrombus, calcification, or ulceration are also

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noted. Finally, attention is given to the organs and viscera of the abdomen and pelvis. Comments about the presence or absence of a normal appearance to the abdominal organs, which are completely visualized on a CT examination, are necessary as incidental findings are routinely present and may have serious implications. Clinical Applications The clinical indications and utility of CTA closely mirror that of MRA, with a few exceptions as outlined below.

Atherosclerotic Peripheral Artery Disease The approach with CTA is identical to that outlined in evaluating MRA images with regard to outlining in detail the qualitative and quantitative aspects of length, lesion severity, and location of stenosis, as these findings have a direct bearing on choice of therapy. CTA assessment of the degree of stenosis in the distal vessels in diabetics and patients with long-standing end-stage renal disease may be limited by calcification, which is often present (Figure 13.15).

Vasculitis Buerger’s disease typically affects the small- to medium-sized arteries of the extremities and primarily affects young male smokers as detailed earlier. The distal nature of the disease

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may favor CTA in light of the submillimeter resolution of the technique. On the other hand, the presence of extensive collaterals may result in the vessels not being completely opacified during the scan. Polyarteritis nodosa typically presents with nonspecific vascular symptoms and is strongly associated with hepatitis B infection [73]. When vascular involvement is present, it is usually restricted to the visceral vessels and CT angiography may be better suited in light of superior spatial resolution. Figure 13.16 shows a severity of iliac disease in a patient with giant-cell arteritis. Drug-induced vasculitis is often seen in patients engaged in recreational drug use as well as patients on certain medical therapies. The narcotic drugs most often associated with vasculitis are amphetamine derivatives and cocaine [74,75]. These patients usually present with vascular stenosis without significant atherosclerotic plaque burden and are often younger. The small- to mediumsized vessels are typically affected. CTA is particularly useful in this patient group as it allows for accurate assessment of vessel wall thickness and inflammation.

Aneurysms and Endovascular Stent Evaluation CTA is commonly used for the initial sizing of AAA’s and peripheral aneurysms, partly related to the ready availability and familiarity of surgeons with CTA (Figure 13.17). Preoperative evaluation of the neck of the aneurysm, the proximal and distal landing zones, as well as the site of percutaneous entry can help determine preferred method of repair. Following endovascular stent placement, follow-up is needed to assure decompression of the aneurysm sac, decrease in aneurysm size, and maintenance of proper

F i g u re 1 3 . 1 5 â•… 3-dimensional volume-rendered image of the lower

extremity shows severe 3-vessel atherosclerotic disease. Areas of luminal calcification can be seen in the anterior tibial, posterior tibial, and peroneal arteries on the axial image (inset). With permission from Ref. 5.

F i g u re 1 3 . 1 6 â•… 3-dimensional volume-rendered computed tomography angiography image showing occlusion of the bilateral common iliac arteries in a patient with giant-cell arteritis. With permission from Ref. 5.

2 2 4Multimodality Imaging in Cardiovascular Medicine

F i g u re 1 3 . 1 7 â•… 3-dimensional volume-rendered computed tomography

angiography image showing a distal left common iliac artery aneurysm. With permission from Ref. 5.

stent position [76,77]. In addition, CTA can also be used to assess for any complications at the percutaneous site [78]. Endoleaks commonly occur in up to 10% to 20% of patients with endovascular stent repairs for abdominal aortic aneurysms and CTA is often the preferred modality to assess this complication [79]. This can be done by acquiring images in the arterial phase as well as a delayed venous phase (approximately 60 seconds after contrast injection) [80]. CTA may be used for evaluation of in-stent restenosis particularly in proximal vessels such as the iliac and femoral arteries (Figure 13.18). This may require reconstruction with alternate kernels and adjustment of window levels. There is currently no prospective or accumulated retrospective evidence evaluating peripheral stents. From clinical experience, CTA has a good negative predictive value for in-stent stenosis, but its specificity for the degree of narrowing, when present, is lacking. When the radiation dose is not prohibitive, increasing the tube current can reduce the metallic artifact.

Other Indications A variety of other conditions may represent less common indications for the execution of a peripheral CTA. For instance, AVMs and fistulas may be well delineated by acquiring images during the arterial and venous phase; however, the lack of dynamic evaluation is a definite disadvantage. CTA imaging may significantly contribute to the characterization of congenital abnormalities with direct or

F i g u re 1 3 . 1 8 â•… Axial and curved multiplanar reconstruction (inset) images of a left common iliac artery stent graft. Axial image allows for proper evaluation of the instent lumen. With permission from Ref. 5.

indirect involvement of the peripheral vessels. The persistent sciatic artery, for instance, represents a rare congenital disorder in which the thigh and popliteal arteries derive their blood supply predominantly from the internal iliac artery. The native SFA, although present, will frequently occlude within the mid thigh, causing these patients to complain of leg pain that worsens with sitting. Artifacts and Pitfalls The reconstruction of CTA images reproducing invasive angiography-like display of the vasculature may help in the interpretation of multiple vascular territories. It is crucial to evaluate the images always keeping in mind the corresponding clinical context and the potential therapeutic options. The most frequent pitfall encountered during the interpretation of CTA images is represented by the difficulty in the evaluation of vascular segments affected by moderate-tosevere calcification or occupied by a stent. The selection of the adequate windowing set (1500 window width) may help in reducing the unavoidable blooming effect produced by structures with high signal attenuation. Cross-sectional MPR images of the vessel of interest are very helpful in visualizing, at least in part, the underlying lumen in the presence of intense calcification or stent. Other interpretation pitfalls such as pseudostenosis or pseudo-occlusions may potentially be generated by inadequate image postprocessing (eg, partial or total vessel removal during MIP image editing and inaccurate centerline definition in CPR images).

CH A PTER 13

•

Claudication

jâ•… DUPLEX U LTRASONOG RAPHY Duplex ultrasonography is very helpful in identifying areas of vascular trauma, specifically iatrogenic. Pseudoaneurysms occur in up to 7.5% of femoral artery catheterizations and can result in complications, including distal embolization, extrinsic compression, rupture, and hemorrhage [81]. Duplex ultrasonography can rapidly and accurately identify these lesions and help guide placement of thrombin to pharmacologically occlude the lesion. In patients who have undergone peripheral bypass graft revascularization, graft stenoses will develop in of 21% to 33% of cases. Once the graft becomes thrombosed, secondary patency rates are dismal. If the stenosis is detected and repaired prior to graft thrombosis, it is estimated that 80% of grafts will be salvaged. A duplex-guided graft surveillance program is a well-validated and evidence-based approach for preserving patency of peripheral bypass grafts. Venous bypass grafts should be studied within 7 days of surgery, and then in 1 month, followed by 3-month intervals for the first year. If the graft remains normal after year 1, followup surveillance should be done every 6 months thereafter. Ankle pressures and waveforms should be performed at the time of each surveillance study. The development of a stenosis during a surveillance examination should prompt consideration toward MRA or CTA, keeping in mind that clip artifact may pose problems with both modalities.

jâ•…C HOICE OF IMAGIN G MODALITY IN THE ASSESSMENT OF PAD The choice between MRA versus CTA versus ultrasound often depends on the disease entity being studied, comorbidities (eg, renal dysfunction), prior endovascular intervention (eg, stents), technical expertise available at the institution, patient tolerability, and finally physician familiarity. For the assessment of atherosclerotic PAD, the few studies that have examined CTA versus MRA have concluded that both modalities are broadly comparable [37]. The image interpretation time required for CTA is significantly higher than that for MRA, largely due to the presence of calcification within the vessels of interest. Calcifications are not a problem in MR, nor are the bony structures, which are subtracted from the images. On the other hand, stent artifacts (non-nitinol) in lower extremity vessels continue to create artifacts with MRA imaging and must be considered when planning a lower extremity imaging evaluation. Similarly patients with pacemakers are effectively excluded from having an MRA. At the present time, the choice of MRA or CTA for the evaluation of PAD will depend largely on scanner availability, with MR preferred in general, and particularly in patients with preexisting mild to moderate renal insufficiency or iodinated contrast allergy. Recently, the issue of NSF has mandated that Gd be used with caution in patients

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with advanced renal disease (GFR <30). In most of these same cases, CTA is also relatively contraindicated, unless the patient is already on dialysis. MRA has an additional advantage in light of newly available noncontrast imaging approaches that may provide the required information.

jâ•… FU T URE DEVELOPMENTS MR angiographic imaging at 3 Tesla (3T) has been increasingly used over the past 5 years and several authors have reported success. A 2-fold higher SNR is the main Â�advantage of using a 3T scanner, which is particularly advantageous when used along with parallel imaging techniques. This combination can allow for high SNR, isometric submillimeter spatial resolution and decreased scan times. Previous studies have shown that faster image times with otherwise unchanged parameters lead to improved image quality due to decreased blurring from motion [82–84]. Dual-energy CT scanners hold the promise of providing bone-free angiograms that may assist in the interpretation of voluminous CT data typically associated with peripheral CT studies. The applicability of this technology for atheroma tissue characterization remains to be tested systemically. The use of 128 or higher slice scanners may allow further reduction of radiation and even better imaging acquisition time; however, the latter is of limited value in CTA exams for assessment of PAD.

jâ•… S U MMARY Each imaging modality has strengths and weaknesses, and a knowledge of these can help the clinician determine the best modality (Table 13.5) [85]. MRA of the abdominal, pelvic, and lower extremity vasculature can be rapidly performed and is ideal for the evaluation of known PAD or claudication symptoms. Images produced are reliable and reproducible with details that are comparable and sometimes superior to conventional DSA. In addition, there are no complications of arterial puncture as with DSA or concerns over radiation as with CTA and DSA. Although there are limitations with metallic implants and imaging certain stented segments, new sequences are allowing better visualization. Future improvements in hardware and software technology will enable further refinements in this technique, making it even more appealing. CT technology has continued to evolve and its application for the diagnosis of diseases of the lower extremities has gained momentum. There are multiple publications of clinical studies documenting its accuracy when compared with other modalities [69]. Although the attenuation from severe calcium deposition and stents are potential limitations, the high spatial resolution, ability to use alternate

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jâ•… Table 13.5â•… Advantages and disadvantages of computed tomography angiography and magnetic resonance angiography Advantages

Disadvantages

Computed tomography angiography

• Short scanning time • Low operator dependency • Widespread availability • High spatial resolution

• Radiation exposure • Contrast nephrotoxicity • Reduced accuracy in calcified vessels

Magnetic resonance angiography

• Good contrast safety profile • Optimal delineation of vessel wall • Dynamic flow information (time-resolved imaging)

• Technically challenging • Contraindication with certain metallic implants • Risk of nephrogenic systemic fibrosis when Gd used in patients with GFR ,30 • Requires patient cooperation

Conventional

• High spatial resolution

• Invasive arterial procedure

Angiography

• Widely available • Not affected by calcium • Immediate intervention if needed

• Radiation exposure • Contrast nephrotoxicity • 2-Dimensional imaging • Vessel wall not assessed

Duplex

• Safe

• Operator dependent

Ultrasonography

• Low cost • Ease of repeatability

• Difficult in obese patients • Lengthy exam

software kernels, and rapid throughput of CTA has enabled its widespread acceptance into evaluation of such patients. CTA is now routinely used in clinical practice and rivals MR angiography for evaluation of vascular Â�disease [37]. Both modalities have enjoyed significant technical advancements that now enable either technology to accurately and noninvasively image the lower extremity vasculature with more comfort and less expense than DSA [37,86]. Although lacking the 3D visualization of MRA and CTA, duplex ultrasonography has especially important applications in the diagnosis and management of iatrogenic vascular trauma, such as arterial pseudoaneurysms, and in the surveillance of patients with peripheral arterial bypass grafts.

jâ•… REC OMMENDED READING Hirsch AT, Haskal ZJ, Hertzer NR et al. ACC/AHA task force on practice guidelines (Writing Committee to develop guidelines for the management of patients with PAD; American Association of Cardiovascular and Pulmonary Rehabilitation; National Heart, Lung, and Blood Institute; Society for Vascular Nursing; TransAtlantic Inter-Society Consensus; Vascular Disease Foundation.)

ACC/AHA 2005 Practice Guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): Circulation. 2006;113(11):e463–e654. Mukherjee D, Rajagopalan S. CT and MR Angiography of the Peripheral Circulation. 1st ed. London, England: Informa Healthcare; 2007.

jâ•… References â•‡ 1. Comerota AJ. Endovascular and surgical revascularization for patients with intermittent claudication. Am J Cardiol. 2001;87:34D–43D. â•‡ 2. Criqui MH. Peripheral arterial disease—epidemiological aspects. Vasc Med. 2001;6:3–7. â•‡ 3. Criqui MH, Denenberg JO, Langer RD, Fronek A. The epidemiology of peripheral arterial disease: importance of identifying the population at risk. Vasc Med. 1997;2:221–226. â•‡ 4. Ridker PM, Stampfer MJ, Rifai N. Novel risk factors for systemic atherosclerosis: a comparison of C-reactive protein, fibrinogen, homocysteine, lipoprotein(a), and standard cholesterol screening as predictors of peripheral arterial disease. JAMA. 2001;285:2481–2485. â•‡ 5. Mukherjee D, Rajagopalan S. CT and MR Angiography of the Peripheral Circulation. 1st ed. London, England: Informa Healthcare; 2007. â•‡ 6. Imparato AM, Kim GE, Davidson T, Crowley JG. Intermittent claudication: its natural course. Surgery. 1975;78:795–799. â•‡ 7. Duprez D. Natural history and evolution of peripheral obstructive arterial disease. Int Angiol. 1992;11:165–168.

CH A PTER 13

•

Claudication

â•‡ 8. Cimminiello C. PAD. Epidemiology and pathophysiology. Thromb Res. 2002;106:V295–V301. â•‡ 9. Hirsch AT, Criqui MH, Treat-Jacobson D, et al. Peripheral arterial disease detection, awareness, and treatment in primary care. JAMA. 2001;286:1317–1324. 10. Criqui MH, Denenberg JO, Bird CE, Fronek A, Klauber MR, Langer RD. The correlation between symptoms and non-invasive test results in patients referred for peripheral arterial disease testing. Vasc Med. 1996;1:65–71. 11. Ouriel K, McDonnell AE, Metz CE, Zarins CK. Critical evaluation of stress testing in the diagnosis of peripheral vascular disease. Surgery. 1982;91:686–693. 12. Treiman GS, Lawrence PF, Galt SW, Kraiss LW. Revision of reversed infrainguinal bypass grafts without preoperative arteriography. J Vasc Surg. 1997;26:1020–1028. 13. Idu MM, Buth J, Hop WC, Cuypers P, van de Pavoordt ED, Tordoir JM. Vein graft surveillance: is graft revision without angiography justified and what criteria should be used? J Vasc Surg. 1998;27:399–411. 14. Wang Y, Winchester PA, Khilnani NM, et al. Contrast-enhanced peripheral MR angiography from the abdominal aorta to the pedal arteries: combined dynamic two-dimensional and bolus-chase threedimensional acquisitions. Invest Radiol. 2001;36:170–177. 15. Tongdee R, Narra VR, McNeal G, et al. Hybrid peripheral 3D contrast-enhanced MR angiography of calf and foot vasculature. AJR Am J Roentgenol. 2006;186:1746–1753. 16. Berg F, Bangard C, Bovenschulte H, et al. Feasibility of peripheral contrast-enhanced magnetic resonance angiography at 3.0 Tesla with a hybrid technique: comparison with digital subtraction angiography. Invest Radiol. 2008;43:642–649. 17. Dinter DJ, Neff KW, Visciani G, et al. Peripheral bolus-chase MR angiography: analysis of risk factors for nondiagnostic image quality of the calf vessels—a combined retrospective and prospective study. AJR Am J Roentgenol. 2009;193:234–240. 18. Kaufman JA, McCarter D, Geller SC, Waltman AC. Two-dimensional time-of-flight MR angiography of the lower extremities: artifacts and pitfalls. AJR Am J Roentgenol. 1998;171:129–135. 19. Laub GA. Time-of-flight method of MR angiography. Magn Reson Imaging Clin N Am. 1995;3:391–398. 20. Li W, Zhang M, Sher S, Edelman RR. MR angiography of the vascular tree from the aorta to the foot: combining two-dimensional time-of-flight and three-dimensional contrast-enhanced imaging. J Magn Reson Imaging. 2000;12:884–889. 21. Baum RA, Rutter CM, Sunshine JH, et al. Multicenter trial to evaluate vascular magnetic resonance angiography of the lower extremity. American College of Radiology Rapid Technology Assessment Group. JAMA. 1995;274:875–880. 22. McCauley TR, Monib A, Dickey KW, et al. Peripheral vascular occlusive disease: accuracy and reliability of time-of-flight MR angiography. Radiology. 1994;192:351–357. 23. Owen RS, Carpenter JP, Baum RA, Perloff LJ, Cope C. Magnetic resonance imaging of angiographically occult runoff vessels in peripheral arterial occlusive disease. N Engl J Med. 1992;326:1577–1581. 24. Collidge TA, Thomson PC, Mark PB, et al. Gadolinium-enhanced MR imaging and nephrogenic systemic fibrosis: retrospective study of a renal replacement therapy cohort. Radiology. 2007;245:168–175. 25. Kallen AJ, Jhung MA, Cheng S, et al. Gadolinium-containing magnetic resonance imaging contrast and nephrogenic systemic fibrosis: a case-control study. Am J Kidney Dis. 2008;51:966–975. 26. Miyazaki M, Sugiura S, Tateishi F, Wada H, Kassai Y, Abe H. Non-contrast-enhanced MR angiography using 3D ECGsynchronized half-Fourier fast spin echo. J Magn Reson Imaging. 2000;12:776–783. 27. Lim RP, Hecht EM, Xu J, et al. 3D nongadolinium-enhanced ECGgated MRA of the distal lower extremities: preliminary clinical experience. J Magn Reson Imaging. 2008;28:181–189. 28. Miyazaki M, Lee VS. Nonenhanced MR angiography. Radiology. 2008;248:20–43. 29. Miyazaki M, Takai H, Sugiura S, Wada H, Kuwahara R, Urata J. Peripheral MR angiography: separation of arteries from veins

227

with flow-spoiled gradient pulses in electrocardiography-triggered three-dimensional half-Fourier fast spin-echo imaging. Radiology. 2003;227:890–896. 30. Lichy MP, Wietek BM, Mugler JP III, et al. Magnetic resonance imaging of the body trunk using a single-slab, 3-dimensional, T2-weighted turbo-spin-echo sequence with high sampling efficiency (SPACE) for high spatial resolution imaging: initial clinical experiences. Invest Radiol. 2005;40:754–760. 31. Mugler JP III, Bao S, Mulkern RV, et al. Optimized single-slab three-dimensional spin-echo MR imaging of the brain. Radiology. 2000;216:891–899. 32. Park J, Mugler JP III, Horger W, Kiefer B. Optimized T1-weighted contrast for single-slab 3D turbo spin-echo imaging with long echo trains: application to whole-brain imaging. Magn Reson Med. 2007;58:982–992. 33. Mihai G, Chung Y-C, Kariisa M, Raman SV, Simonetti OP, Rajagopalan S. Initial feasibility of a multi-station high resolution 3D dark blood angiography protocol for the assessment of peripheral arterial disease. J Magn Res Imaging. 2009;30(4):785–793. 34. Fenchel M, Scheule AM, Stauder NI, et al. Atherosclerotic disease: whole-body cardiovascular imaging with MR system with 32 receiver channels and total-body surface coil technology—initial clinical results. Radiology. 2006;238:280–291. 35. Gjonnaess E, Morken B, Sandbaek G, et al. Gadolinium-enhanced magnetic resonance angiography, colour duplex and digital subtraction angiography of the lower limb arteries from the aorta to the tibio-peroneal trunk in patients with intermittent claudication. Eur J Vasc Endovasc Surg. 2006;31:53–58. 36. Janka R, Fellner C, Wenkel E, Lang W, Bautz W, Fellner FA. Contrastenhanced MR angiography of peripheral arteries including pedal vessels at 1.0 T: feasibility study with dedicated peripheral angiography coil. Radiology. 2005;235:319–326. 37. Collins R, Cranny G, Burch J, et al. A systematic review of duplex ultrasound, magnetic resonance angiography and computed tomography angiography for the diagnosis and assessment of symptomatic, lower limb peripheral arterial disease. Health Technol Assess. 2007;11:iii-iv, xi-xiii, 1–184. 38. Steffens JC, Schafer FK, Oberscheid B, et al. Bolus-chasing contrastenhanced 3D MRA of the lower extremity. Comparison with intraarterial DSA. Acta Radiol. 2003;44:185–192. 39. Vavrik J, Rohrmoser GM, Madani B, Ersek M, Tscholakoff D, Bucek RA. Comparison of MR angiography versus digital subtraction angiography as a basis for planning treatment of lower limb occlusive disease. J Endovasc Ther. 2004;11:294–301. 40. Sueyoshi E, Sakamoto I, Matsuoka Y, et al. Aortoiliac and lower extremity arteries: comparison of three-dimensional dynamic contrast-enhanced subtraction MR angiography and conventional angiography. Radiology. 1999;210:683–688. 41. Kreitner KF, Kalden P, Neufang A, et al. Diabetes and peripheral Â�arterial occlusive disease: prospective comparison of contrastenhanced three-dimensional MR angiography with conventional digital subtraction angiography. AJR Am J Roentgenol. 2000;174: 171–179. 42. Dorweiler B, Neufang A, Kreitner KF, Schmiedt W, Oelert H. Magnetic resonance angiography unmasks reliable target vessels for pedal bypass grafting in patients with diabetes mellitus. J Vasc Surg. 2002;35:766–772. 43. Hofmann WJ, Forstner R, Kofler B, Binder K, Ugurluoglu A, Magometschnigg H. Pedal artery imaging—a comparison of selective digital subtraction angiography, contrast enhanced magnetic resonance angiography and duplex ultrasound. Eur J Vasc Endovasc Surg. 2002;24:287–292. 44. Carriero A, Maggialetti A, Pinto D, et al. Contrast-enhanced magnetic resonance angiography MoBI-trak in the study of peripheral vascular disease. Cardiovasc Intervent Radiol. 2002;25:42–47. 45. Leiner T, Kessels AG, Schurink GW, et al. Comparison of contrastenhanced magnetic resonance angiography and digital subtraction angiography in patients with chronic critical ischemia and tissue loss. Invest Radiol. 2004;39:435–444.

228

46. Bertschinger K, Cassina PC, Debatin JF, Ruehm SG. Surveillance of peripheral arterial bypass grafts with three-dimensional MR angiography: comparison with digital subtraction angiography. AJR Am J Roentgenol. 2001;176:215–220. 47. Berkowitz HD, Hobbs CL, Roberts B, Freiman D, Oleaga J, Ring E. Value of routine vascular laboratory studies to identify vein graft stenosis. Surgery. 1981;90:971–979. 48. Cejna M, Loewe C, Schoder M, et al. MR angiography vs CT angiography in the follow-up of nitinol stent grafts in endoluminally treated aortic aneurysms. Eur Radiol. 2002;12:2443–2450. 49. Ayuso JR, de Caralt TM, Pages M, et al. MRA is useful as a follow-up technique after endovascular repair of aortic aneurysms with nitinol endoprostheses. J Magn Reson Imaging. 2004;20:803–810. 50. Haulon S, Lions C, McFadden EP, et al. Prospective evaluation of magnetic resonance imaging after endovascular Â�treatment of infrarenal aortic aneurysms. Eur J Vasc Endovasc Surg. 2001;22:62–69. 51. Cohen EI, Weinreb DB, Siegelbaum RH, et al. Time-resolved MR angiography for the classification of endoleaks after endovascular aneurysm repair. J Magn Reson Imaging. 2008;27:500–503. 52. Olin JW, Shih A. Thromboangiitis obliterans (Buerger’s disease). Curr Opin Rheumatol. 2006;18:18–24. 53. Suzuki. Angiographic findings in Buerger disease. Int J Cardiol. 1996;54:189–195. 54. Laird JR. The management of acute limb ischemia: techniques for dealing with thrombus. J Interv Cardiol. 2001;14:539–546. 55. Varga ZA, Locke-Edmunds JC, Baird RN. A multicenter study of popliteal aneurysms. Joint Vascular Research Group. J Vasc Surg. 1994;20:171–177. 56. Harder Y, Notter H, Nussbaumer P, Leiser A, Canova C, Furrer M. Popliteal aneurysm: diagnostic workup and results of surgical treatment. World J Surg. 2003;27:788–792. 57. Halliday AW, Taylor PR, Wolfe JH, Mansfield AO. The management of popliteal aneurysm: the importance of early surgical repair. Ann R Coll Surg Engl.1991;73:253–257. 58. Dawson I, Sie RB, van Bockel JH. Atherosclerotic popliteal aneurysm. Br J Surg. 1997;84:293–299. 59. Honjo O, Yamada Y, Kuroko Y, Kushida Y, Une D, Hioki K. Spontaneous dissection and rupture of common iliac artery in a patient with fibromuscular dysplasia: a case report and review of the literature on iliac artery dissections secondary to fibromuscular dysplasia. J Vasc Surg. 2004;40:1032–1036. 60. Onal B, Ilgit ET, Akpek S, Erbas G, Akkaya A. Endovascular treatment of obstructive iliac artery dissections. Acta Radiol. 2005;46:359–365. 61. Thalhammer C, Kirchherr AS, Uhlich F, Waigand J, Gross CM. Postcatheterization pseudoaneurysms and arteriovenous fistulas: repair with percutaneous implantation of endovascular covered stents. Radiology. 2000;214:127–131. 62. Desai MY, Stone JH, Foo TK, Hellmann DB, Lima JA, Bluemke DA. Delayed contrast-enhanced MRI of the aortic wall in Takayasu’s arteritis: initial experience. AJR Am J Roentgenol. 2005;184:1427–1431. 63. Nuenninghoff DM, Warrington KJ, Matteson EL. Concomitant giant cell aortitis, thoracic aortic aneurysm, and aortic arch syndrome: occurrence in a patient and significance. Arthritis Rheum. 2003;49:858–861. 64. Narvaez J, Narvaez JA, Nolla JM, Sirvent E, Reina D, Valverde J. Giant cell arteritis and polymyalgia rheumatica: usefulness of vascular magnetic resonance imaging studies in the diagnosis of aortitis. Rheumatology (Oxford). 2005;44:479–483. 65. Radford DJ, Pohlner PG. The middle aortic syndrome: an important feature of Williams’ syndrome. Cardiol Young. 2000;10:597–602. 66. Daniels SR, Loggie JM, Schwartz DC, Strife JL, Kaplan S. Systemic hypertension secondary to peripheral vascular anomalies in patients with Williams syndrome. J Pediatr. 1985;106:249–251. 67. Fowl. Popliteal artery entrapment. In: Rutherford, ed. Vascular Surgery. Philadelphia, PA: Saunders; 2000:1087–1093.

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68. Wright LB, Matchett WJ, Cruz CP, et al. Popliteal artery disease: diagnosis and treatment. Radiographics. 2004;24:467–479. 69. Met R, Bipat S, Legemate DA, Reekers JA, Koelemay MJ. Diagnostic performance of computed tomography angiography in peripheral arterial disease: a systematic review and meta-analysis. JAMA. 2009;301:415–424. 70. Nakayama Y, Awai K, Funama Y, et al. Lower tube voltage reduces contrast material and radiation doses on 16-MDCT aortography. AJR Am J Roentgenol. 2006;187:W490–W497. 71. Iezzi R, Cotroneo AR, Filippone A, Giancristofaro D, Storto ML. Four-detector row computed tomographic angiography in the evaluation of infrarenal aorta and peripheral arterial occlusive disease: influence of contrast medium concentration. J Comput Assist Tomogr. 2008;32:690–696. 72. Sigal-Cinqualbre AB, Hennequin R, Abada HT, Chen X, Paul JF. Lowkilovoltage multi-detector row chest CT in adults: feasibility and effect on image quality and iodine dose. Radiology. 2004;231:169–174. 73. Guillevin L, Mahr A, Callard P, et al. Hepatitis B virus-associated polyarteritis nodosa: clinical characteristics, outcome, and impact of treatment in 115 patients. Medicine (Baltimore). 2005;84:313–322. 74. Krendel DA, Ditter SM, Frankel MR, Ross WK. Biopsy-proven cerebral vasculitis associated with cocaine abuse. Neurology. 1990;40:1092–1094. 75. Brust JC. Vasculitis owing to substance abuse. Neurol Clin. 1997;15:945–957. 76. Waasdorp EJ, de Vries JP, Sterkenburg A, et al. The association between iliac fixation and proximal stent-graft migration during EVAR follow-up: mid-term results of 154 Talent devices. Eur J Vasc Endovasc Surg. 2009;37:681–687. 77. Upchurch G. Abdominal aortic aneurysms. In: Rajagopalan S, Mukherjee D, Mohler ERI, eds. Manual of Vascular Diseases. Philadelphia, PA: Lippincott Williams and Wilkins; 2005:437. 78. Bent CL, Fotiadis N, Renfrew I, et al. Total percutaneous aortic repair: midterm outcomes. Cardiovasc Intervent Radiol. 2009;32:449–454. 79. Upchurch GR Jr., Eliason JL, Rectenwald JE, Escobar G, Kabbani L, Criado E. Endovascular abdominal aortic aneurysm repair versus open repair: why and why not? Perspect Vasc Surg Endovasc Ther. 2009;21:48–53. 80. Stolzmann P, Frauenfelder T, Pfammatter T, et al. Endoleaks after endovascular abdominal aortic aneurysm repair: detection with dualenergy dual-source CT. Radiology. 2008;249:682–691. 81. Kresowik TF, Khoury MD, Miller BV, et al. A prospective study of the incidence and natural history of femoral vascular complications after percutaneous transluminal coronary angioplasty. J Vasc Surg. 1991;13:328–333, discussion 33–5. 82. Born M, Willinek WA, Gieseke J, von Falkenhausen M, Schild H, Kuhl CK. Sensitivity encoding (SENSE) for contrast-enhanced 3D MR angiography of the abdominal arteries. J Magn Reson Imaging. 2005;22:559–565. 83. Michaely HJ, Herrmann KA, Kramer H, et al. High-resolution renal MRA: comparison of image quality and vessel depiction with different parallel imaging acceleration factors. J Magn Reson Imaging. 2006;24:95–100. 84. Schoenberg SO, Bock M, Knopp MV, et al. Renal arteries: optimization of three-dimensional gadolinium-enhanced MR angiography with bolus-timing-independent fast multiphase acquisition in a single breath hold. Radiology. 1999;211:667–679. 85. Dellegrottaglie S, Sanz J, Macaluso F, Einstein AJ, Simonetti OP, Rajagopalan S. Technology insight: magnetic resonance angiography for the evaluation of patients with peripheral artery disease. Nat Clin Pract Cardiovasc Med. In press. 86. Levin DC, Rao VM, Parker L, Frangos AJ, Sunshine JH. The effect of the introduction of MR and CT angiography on the utilization of catheter angiography for peripheral arterial disease. J Am Coll Radiol. 2007;4:457–460.

14

Preoperative Risk Stratification

Ra dosav V idakovi c´ Do n Polder mans

Early or late perioperative cardiovascular morbidity and mortality are among the major problems in patients undergoing noncardiac surgery. It is estimated that of almost 40 million annually performed surgical procedures in Europe, cardiovascular mortality occurs in 0.3%, and postoperative myocardial infarction (MI) in 1%. In a pooled analysis of unselected noncardiac surgery patients over the age of 40 years, a 30-day incidence of postoperative cardiac events (MI and cardiac death) was 2.5% [1]. The rate of these events is even higher in vascular surgery patients (6.2%) [2]. The true event rate of postoperative cardiac complications can be even higher, since most of them occur asymptomatically and depend on the type of postoperative surveillance (Figure 14.1) [3,4]. The majority of postoperative cardiac complications are caused by sudden or prolonged myocardial ischemia due to a primary coronary event (such as plaque erosion and/or rupture, fissuring, or dissection) or due to either increased oxygen demand or decreased supply (such as coronary artery spasm, coronary embolism, anemia, arrhythmias, hypertension, or hypotension) [5,6]. Other

F i G U re 1 4 . 1 â•… The incidence of perioperative cardiac events in noncardiac surgery [4].

major determinants of adverse postoperative outcome are aortic stenosis and left ventricular dysfunction [7–9]. The pathophysiology of cardiac events in these 2 conditions is related to an interaction of developing hypotension and low cardiac output during surgery, and possible underlying coronary artery disease (CAD). To reduce postoperative cardiac morbidity and mortality, preoperative screening is of paramount importance. This screening involves identification of potential risk factors, as well as different noninvasive imaging modalities. In this chapter we will describe the current status of preoperative risk stratification for patients undergoing noncardiac surgery.

jâ•… EST IMATION OF CARDIAC RISK Identification of clinical risk factors, which can predict postoperative cardiac complications, was of great interest for the past 30 years. For that purpose, several risk indices were developed, such as Goldman cardiac risk index, the Detsky modified multifactorial risk index, Eagle’s risk score, American Society of Anesthesiologist index, and Canadian Cardiovascular Society index [10–14]. In direct comparison of these risk indices in 2035 patients, who underwent elective or urgent noncardiac surgery, Gilbert et al showed that they all performed better than chance [15]. However, no index was significantly superior to the other. The recently published revision of Goldman’s risk index by Lee et al named Revised Cardiac Risk Index, substantially improved its predictive value [16]. By identifying 6 predictors of major postoperative cardiac complications (ischemic heart disease, congestive heart failure, cerebrovascular disease, diabetes mellitus treated with insulin, renal failure, and high-risk surgery), this risk index stratifies patients in 4 categories: with 0, 1, 2, and $3 risk factors. The estimated rates for postoperative major cardiac complications in each group are 0.4%, 0.9%, 7%, and 11%, respectively. Boersma et al validated the Lee risk index in a large cohort of 108â•›593 patients who underwent all types of noncardiac surgical procedures, including vascular surgical procedures, and demonstrated a substantial improvement by adding the surgical risk of the various procedures [17]. 229

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The American College of Cardiology (ACC) and the American Heart Association (AHA) guidelines on perioperative cardiovascular evaluation and care for noncardiac surgery provide the stepwise algorithm to preoperative cardiac assessment [18]. This algorithm uses the urgency of noncardiac surgery, clinical risk factors, and patients’ functional capacity in prediction of postoperative cardiac events. Clinical risk factors are divided into 3 categories: major, intermediate, and minor risk factors (Table 14.1). In contrast to the previous edition of these guidelines, the category of intermediate-risk factors is substituted by the risk factors included in Revised Cardiac Risk Index, with the exclusion of the type of surgery, which is incorporated elsewhere in the algorithm (Table 14.2). The first step in this algorithm is to determine the urgency of noncardiac surgery. Patients needing emergency noncardiac surgery should proceed to surgery without the delay of additional cardiac evaluation, with the instructions for postoperative surveillance and risk factor management. The next few steps refer to the patients considered for elective noncardiac surgery: (a) In the presence of active cardiac conditions, the surgery should be canceled or delayed until the cardiac problem has been clarified and treated appropriately. (b) Patients scheduled for the low-risk surgery (reported cardiac risk generally ,1%) and good functional capacity, or diminished functional capacity but no risk factors, should proceed with planned surgery. (c) Patients scheduled for intermediate-risk surgery (reported cardiac risk generally 1%–5%) or high-risk surgery (reported cardiac risk generally .5%), with poor or unknown functional capacity and 1 to 2 clinical risk factors, should proceed with the planned surgery with tight heart rate control using beta-blockers, or to preoperative testing if that will change management; the same applies to the patients scheduled for intermediate-risk surgery, poor or unknown functional capacity, and $3 risk factors. (d) Patients scheduled for high-risk surgery (reported cardiac risk generally .5%), poor or unknown functional capacity, and $3 risk factors should be considered for preoperative testing if it will change management.

jâ•… ADD ITIONAL TESTING Further cardiac testing is warranted only if the test results will change perioperative management. Besides the fact that preoperative noninvasive testing increases cost of treatment of noncardiac surgery patients, it also might delay surgery and run the risk of. Although there is no doubt that high-risk patients ($3 risk factors and poor functional capacity) should be further evaluated by noninvasive testing, the question whether it can be omitted in intermediate-risk patients (1 or 2 risk factors) remains open.

Multimodality Imaging in Cardiovascular Medicine

jâ•… Table 14.1â•… Clinical predictors of increased perioperative cardiovascular risk [18] Major predictors—active cardiac conditions • Unstable coronary syndromes • Unstable or severe angina • Recent myocardial infarction • Decompensated heart failure • Significant arrhythmias • Severe valvular disease Intermediate predictors* • History of heart disease • History of compensated or prior heart failure • History of cerebrovascular disease • Diabetes mellitus • Renal insufficiency Minor predictors • Advanced age (.70 years) • Abnormal electrocardiogram (left ventricular hypertrophy, left bundle-branch block, ST-T abnormalities) • Rhythm other than sinus • Severe valvular disease *Clinical risk factors from the Revised Cardiac Risk Index, except type of surgery.

Recently published Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echo II (DECREASE II) study tried to resolve this dilemma [3]. Of 1476 screened vascular surgery patients treated with beta-blockers, 770 were identified to be of intermediate-risk for postoperative major cardiac events. These patients were randomly assigned to cardiac stress testing (n 5 386) or no testing. Test results were used to optimize perioperative cardiac care, including optimal heart rate (HR) control in patients with ischemia below the ischemic HR threshold, and coronary revascularization was considered in those with extensive ischemia on test ($5 left ventricular segments). All patients proceeded to planned vascular surgery with beta-blocker therapy aiming at a HR of 60 to 65 beats per minute. Study results showed that patients assigned for no testing had the same incidence of primary end points (cardiac death or nonfatal MI) as those assigned for testing (1.8% vs. 2.3%; P 5 .62), and waited for the vascular surgery intervention almost 3 weeks less. Several imaging modalities can be used for the additional preoperative testing, such as stress echocardiography (SE), myocardial perfusion scintigraphy (MPS), cardiac computed tomography (CCT), and cardiac magnetic resonance (CMR). Stress Echocardiography This diagnostic method is based on the enhancement of myocardial oxygen demand and subsequent ischemia by infusion

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F i g u re 1 4 . 2 â•… Dobutamine stress echocardiography. Quad-screen format of apical 3-chamber view, end-systolic frames at baseline (upper left),

low dose (upper right), peak dose (lower left), and recovery (lower right). At low dose, there is increased systolic wall thickening in all segments indicating improvement in contractility. At peak dose, akinesis of distal septum and apex can be noted; arrows indicate region with absent wall thickening, consistent with ischemic response. Courtesy of Aleksandar N. Neskovic, MD. (University Medical Center, Zemun, Belgrade, Serbia).

of incremental doses of dobutamine, which increases myocardial contractility and HR. Commenced contractile dysfunction in ischemic myocardial segments is assessed by echocardiography as wall motion abnormalities (Figure 14.2). Numerous studies showed SE as being predictive for short- and long-term perioperative cardiac events, with a high negative and moderate positive predictive value [19–26]. The most useful prognostic data obtained during SE are ischemic threshold (ie, the cardiac workload necessary to induce myocardial ischemia), and extent and severity of wall motion abnormalities. The test results are limited in patients on beta-blocker therapy (diminished HR response), and in those with bad image quality. Myocardial Perfusion Scintigraphy Diminished blood flow through the stenotic coronary arteries can be diagnosed using small amounts of intravenously administered radioactive tracers such as thallium 201 or technetium 99m. Perfusion defects are more obvious if recorded during exercise or pharmacologic stress and can be classified

jâ•… Table 14.2â•… Surgery-specific risk of perioperative cardiac events in noncardiac surgery [18] Estimated Risk High • (.5%)

Intermediate • (1%25%)

Low • (,1%)

Type of Surgery • Aortic and other type of major vascular surgery • Any other surgical procedure associated with large fluid shifts and/or blood loss • Carotid endarterectomy • Head and neck surgery • Orthopedic surgery • Prostate surgery • Endoscopic procedures • Superficial procedures • Cataract surgery • Breast surgery • Ambulatory surgery

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as reversible (ischemia) or fixed (scar) (Figure 14.3). This diagnostic technique has been extensively studied in the setting of preoperative risk assessment, showing its high sensitivity but low specificity in predicting postoperative cardiac complications [27–30]. The likelihood of perioperative complications is higher with reversible perfusion defects and increases with its extent [31]. Cardiac Computed Tomography

1 4 . 3 â•…Dipyridamole thallium 201 myocardial perfusion scintigraphy. Lower images were taken at rest and upper images during dipyridamole stress. The arrows indicate the presence of reversible perfusion defect in the lateral wall. Courtesy of Jeroen J. Bax, MD. (Leiden University Medical Center, Leiden, the Netherlands). F i g u re

In the past decade, CCT emerged as a reliable diagnostic method for the assessment of CAD, coronary artery anatomy, and cardiac function (Figures 14.4 and 14.5). Constant technological improvements in the field of CCT (introduction of dual-source and 256-slice CTs) impose it as an excellent alternative to standard coronary angiography in selected group of patients. Studies investigating the accuracy of CCT in detection of obstructive CAD report its sensitivity, specificity, positive and negative predictive value to be 94% to 99%, 95% to 97%, 76% to 97%, and 93% to 99%, respectively [32,33]. Concerning high specificity of CCT reported, it appears as an

F i g u re 1 4 . 4 â•…Cardiac computerized tomography. Coronary angiography in patient with bilateral aorto-illiacal stenosis and previously performed percutaneous coronary intervention with placement of two stents in the right coronary artery. Both stents are of good patency (lower left and right panels). Stenosis of the left descending coronary artery of 50% is indicated by the arrow (upper right panel). Courtesy of Dragan Sagic, MD. (Dedinje Cardiovascular Institute, Belgrade, Serbia).

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F i g u re 1 4 . 5 â•…Cardiac computed tomography. 3-Dimensional reconstruction of coronary angiography in the same patient. Courtesy of Dragan

Sagic, MD. (Dedinje Cardiovascular Institute, Belgrade, Serbia).

excellent diagnostic modality for excluding CAD. In contrast to conventional coronary angiography, CCT allows the assessment of atherosclerotic plaque morphology and identifies unstable plaques [34,35]. The assessment of plaque morphology may have an important role in identifying patients who are at greater perioperative risk for adverse cardiac events. CCT also showed high accuracy in assessing coronary artery graft and stent patency [36–39]. Nevertheless, there are certain limitations to the use of CCT in those settings which can lead to the diminished quality of the images of the grafts and implanted stents (ie, presence of surgical clips, calcifications, and metallic artifacts). Although two-dimensional (2D) echocardiography will remain the preferred tool in preoperative assessment of global left ventricular function and wall motion, CCT showed as accurate tool for this purposes [40]. There are certain limitations of CCT that cannot be ignored. Image acquisition is highly dependent on heart rhythm and rate (motion artifacts), on amount of coronary calcium, and it requires exposing patients to relatively high radiation dose. Above all, the cost of CCT equipment is higher in comparison to other easily available noninvasive imaging modalities, that is, echocardiography. In the light of these limitations remains the question about the prospective candidate for preoperative testing with CCT. To our opinion, the most reasonable will be to use CCT in defining perioperative risk in patients who have positive or

equivocal noninvasive cardiac stress tests, that is, dobutamine SE or MPS. Cardiac Magnetic Resonance The particular interest for CMR in the settings of preoperative risk stratification is based on its excellent possibilities in assessment of ventricular function, myocardial perfusion, and coronary artery anatomy [41–44]. In patients who are not suitable for SE (ie, bad images because of suboptimal acoustic window), stress CMR using dobutamine appears as a good alternative. The protocol for administration of dobutamine and image analysis in stress CMR is similar to dobutamine SE. Studies have shown high accuracy and reproducibility of stress CMR in the detection of wall motion abnormalities [45,46]. In the study by Hundley et al CMR showed excellent performance in the prediction of future cardiac events in patients with inducible ischemia (hazard ratio 3.3, CI: 1.1–9.7) [47]. The same group analyzed the accuracy of stress CMR for preoperative risk assessment [48]. Of the 102 patients referred for noncardiac surgery (29 vascular and 73 nonvascular), myocardial ischemia occurred in 25 patients during dobutamine stress CMR. Postoperative cardiac events (death, nonfatal MI, and congestive heart failure) developed in 5 of those patients, presenting a sensitivity and specificity

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F i g u re 1 4 . 6 â•…Dobutamine stress cardiac magnetic resonance test. Quad-screen format of 4-chamber view, end-systolic frames at baseline

(upper left), 20-μg/kg/min dose (upper right), 30-μg/kg/min dose (lower left), and 40-μg/kg/min (lower right) dobutamine. At lower doses, there is increased systolic wall thickening in all segments indicating improvement in contractility. At 40 μg/kg/min dose, akinesis of apex and lateral wall can be noted; arrows indicate region with absent wall thickening, consistent with ischemic response.

of CMR for the prediction of perioperative cardiac complications of 84% and 78%, respectively. Because of its noninvasive nature, superb image quality, absence of radiation, and application of contrast media, CMR appears to be an excellent cardiovascular imaging modality. The main limitations are complexity of the technique, its cost, and high dependency on the operator expertise (Figure 14.6). jâ•…H OW CAN THE TEST RES U LTS INFLUENC E MANAG EMENT? Patients with estimated intermediate or high risk for perioperative cardiac complications, with normal tests and no stress-induced myocardial ischemia should proceed with the planned surgery. The situation is more complex if the test results are positive and the final decision to operate with the use of optimal cardioprotective therapy or to perform preoperative cardiac revascularization depends mainly on the extent and severity of stress-induced myocardial ischemia.

Cardioprotective Medical Therapy—Beta-Blockers and Statins Cardioprotective effect of beta-blockers is based on the fact that they can diminish the effects of increased sympathetic activity in surgical patients. In DECREASE I trial, 112 selected vascular surgery patients with evidence of myocardial ischemia on preoperative dobutamine SE were randomly assigned to receive placebo or bisoprolol (5–10 mg) [49]. Treatment with bisoprolol was started at least 7 days before surgery. Perioperative bisoprolol use resulted in a 10-fold reduction in the incidence of cardiac death and MI (3.4% vs. 34%; P , .001). Maximum benefit of beta-blocker therapy in vascular surgery patients with CAD can be achieved only if a tight HR control is established. This was proved in a recently published study on 272 vascular surgery patients on chronic beta-blocker therapy [50]. Higher doses of beta-blockers and lower HR were associated with reduced perioperative ischemia detected on ECG Holter monitoring (hazard ratio: 2.49, 95% confidence interval (CI): 1.79–3.48) and troponine T release (hazard ratio: 1.53, 95% CI: 1.16–2.03).

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The beneficial cardioprotective effect of beta-blockers in noncardiac surgery was questioned by the recently published PeriOperative ISchemic Evaluation (POISE) trial [51]. In the trial, 8351 patients were randomly assigned to either controlled-release oral metoprolol succinate or placebo. Fewer patients in the metoprolol group than in the placebo group had an MI (4.2% vs. 5.7% patients; hazard ratio 0.73, CI: 0.60–0.89; P 5 .0017). Nevertheless, the incidence of deaths and stroke in the metoprolol group was higher than that in the placebo group (3.1% vs. 2.3% patients; hazard ratio 1.33, CI: 1.03–1.74; P 5 .0317 for all-cause mortality; 1.0% vs. 0.5% patients; hazard ratio 2.17, CI: 1.26–3.74; P 5 .0053 for stroke). The different outcomes in the POISE trail in comparison to those previously mentioned can be explained by differences in dosing regimens of beta-blockers. Unusually high starting dose of metoprolol succinate in the POISE trial and short initiation time of therapy before surgery might have caused an unfavorable hemodynamic condition that ultimately resulted in higher incidence of all-cause mortality and stroke. Regardless to the POISE trial results, current ACC/ AHA guidelines recommend the use of perioperative betablocker therapy, preferably long-acting agents started days to weeks before elective surgery. Cardioprotective effect of statins is based on their socalled pleiotropic properties (ie, improving endothelial function, enhancing the stability of atherosclerotic plaques, decreasing oxidative stress and inflammation, and inhibiting the thrombogenic response). To evaluate the association between statin use and perioperative mortality, Poldermans et al performed a case-controlled study among patients who underwent major vascular surgery [52]. A cardiovascular complication during the perioperative phase was the primary cause of death in 104 (65%) case subjects. Statin therapy was significantly less common in cases than in controls (8% vs. 25%; Pâ•›, .001). The risk of perioperative mortality among statin users was reduced 4.5 times compared with nonusers (adjusted odds ratio for perioperative mortality among statin users as compared with nonusers was 0.22 [CI: 0.1–0.47]). A prospective, double-blinded placebo-controlled trial by Durazzo et al randomly assigned 100 patients referred for vascular surgery to either 20-mg atorvastatin or placebo for 45 days [53]. After 6 months of follow-up, the incidence of cardiovascular events (death, nonfatal MI, stroke, or unstable angina pectoris) was 3 times lower with atorvastatin than with placebo (8% vs. 26%; P 5 0 031). Coronary Revascularization Prior to Noncardiac Surgery Both percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) are evaluated in purpose of risk reduction in noncardiac surgery patients.

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A study by Posner et al compared cardiac outcomes after noncardiac surgery in patients with prior PCI, patients with non-revascularized CAD, and normal controls [54]. The results showed that patients treated with PCI within 90 days of noncardiac surgery had a similar incidence of perioperative events as matched with patients with CAD who had not been revascularized. Patients who underwent noncardiac surgery more than 90 days after PCI had a lower risk of cardiac events than non-revascularized patients, but not as low as normal controls. However, the effect of revascularization was limited to a reduction in the incidence of angina pectoris and congestive heart failure, and there was no reduction in the incidence of death and nonfatal MI. Apart from these findings, it is also important to note that if PCI procedure and coronary stent placement are performed ,6 weeks before major noncardiac surgery, the risk of Â�perioperative coronary thrombosis or major bleeding complications may be substantially increased [55,56]. The recently published prospective randomized Coronary Artery Revascularization Prophylaxis (CARP) trial comprised 510 patients who were scheduled for elective major vascular surgery and were selected for preoperative CAG if a cardiology consultant considered that there was an increased risk for a perioperative cardiac complications [57]. Patients with at least 70% stenosis of one or more major coronary arteries were randomly assigned to receive either preliminary coronary revascularization (PCI: n 5 141; CABG: n 5 99) plus medical management or medical management alone in conjunction with their elective vascular procedure. The study did not find difference in 30-days mortality rate between patients who had coronary revascularization prior to vascular surgery and those who were treated medically (3.1% vs. 3.4%; P 5 .87). The rate of perioperative nonfatal MI as detected by troponin elevation also did not differ in coronary revascularization patients and patients treated medically (11.6% vs. 14.3%; P 5 .37). Additionally, the late survival rates at median follow-up of 2.7 years did not differ significantly between the patients who were assigned to have preliminary coronary intervention and those who were not (78% vs. 77%). Furthermore, the results of this trial also indicated that coronary revascularization prior to vascular surgery was associated with delay or cancellation of the required vascular operation. However, CARP trial findings may be explained by the fact that the vast majority of included patients had 1- or 2-vessel disease with a preserved left ventricular function and sufficient cardioprotection by medical therapy (betablockers in 85% of all patients, aspirin in 72%, and statins in 53%). Hence, if a beneficial effect of the invasive strategy of prophylactic revascularization is to be expected, then at least patients with extensive CAD should benefit from this strategy. This hypothesis was evaluated in the recently published DECREASE V Pilot study [58]. The total of 101 patients scheduled for elective vascular surgery, with extensive stress-induced ischemia on dobutamine

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SE ($5 ischemic of 17 segments) or MPS ($3 ischemic walls), were randomly assigned to either prophylactic myocardial revascularization (49 patients) or medical therapy (52 patients). A reduced left ventricular ejection fraction (,35%) was observed in 43 (43%) patients. Among the patients allocated to preoperative coronary revascularization, CAG revealed 3-vessel disease in 33 (67%) patients and left main disease in 4 (8%). A PCI was performed in 32 patients and CABG in 17. The 30-day outcome was not improved by myocardial revascularization; the incidence of all-cause mortality or nonfatal MI for patients with Â�preoperative revascularization or medical treatment only was 43% vs. 33%, respectively (P 5 .3). The same was observed for the incidence of 1-year composite end points (revascularization group: 49% vs. medical therapy group: 44%; P 5 .48). Potentially harmful effect of coronary revascularization in high-risk noncardiac surgery patients might arise from 2 reasons: (a) the delaying of planed noncardiac surgery and (b) higher cumulative risk of both coronary revascularization and noncardiac surgery than noncardiac surgery alone. Current ACC/AHA guidelines recommend prophylactic coronary revascularization in noncardiac surgery patients only for cardiac unstable patients.

jâ•… CONCL USIO N Clinical cardiac risk markers, together with the type and urgency of planned surgery, can truly stratify patients in intermediate- and high-risk population. Intermediate-risk patients can probably be operated without any additional noninvasive screening and should be treated with betablockers (aiming HR 60–65 beats per minute) and statins. In addition to intensive medical therapy with beta-blockers and statins, high-risk patients should be screened noninvasively for the extent of underlying CAD if that will change treatment management. The choice of the test should be based on the centers’ experience and short-term availability. Although coronary revascularization did not show significant advantages compared to the medical therapy in high-risk patients, it has to be considered in patients with unstable CAD. In patients who undergo coronary revascularization by PCI with stents, antiplatelet therapy should only be discontinued perioperatively if bleeding risks with increased mortality or sequels are comparable with the observed cardiovascular risks after its withdrawal.

jâ•… ACKNOWLEDG MENT Radosav Vidakovic is supported by unrestricted research grant from Foundation Lijf en Leven, Rotterdam, The Netherlands.

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jâ•… REFERENCES â•‡ 1. Mangano DT. Perioperative cardiac morbidity. Anesthesiology. 1990;72(1):153–184. â•‡ 2. Mackey WC, Fleisher LA, Haider S, et al. Perioperative myocardial ischemic injury in high-risk vascular surgery patients: incidence and clinical significance in a prospective clinical trial. J Vasc Surg. 2006;43(3):533–538. â•‡ 3. Poldermans D, Bax JJ, Schouten O, et al. Should major vascular surgery be delayed because of preoperative cardiac testing in intermediate risk patients receiving beta-blocker therapy with tight heart rate control? J Am Coll Cardiol. 2006;48:964–969. â•‡ 4. Feringa HH, Karagiannis SE, Vidakovic R, et al. The prevalence and prognosis of unrecognized myocardial infarction and silent myocardial ischemia in patients undergoing major vascular surgery. Coron Artery Dis. 2007;18(7):571–576. â•‡ 5. Dawood MM, Gupta DK, Southern J, et al. Pathology of fatal perioperative myocardial infarction: implications regarding pathophysiology and prevention. Int J Cardiol. 1996;57:37–44. â•‡ 6. Warltier DC, Pagel PS, Kersten JR, et al. Approaches to the prevention of perioperative myocardial ischemia. Anesthesiology. 2000;92:253–259. â•‡ 7. Kertai M, Bountioukos M, Boersma E, et al. Aortic stenosis: an underestimated risk factor for perioperative complications in patients undergoing noncardiac surgery. Am J Med. 2004;116(1):8–13. â•‡ 8. Christ M, Sharkova Y, Geldner G, et al. Preoperative and perioperative care for patients with suspected or established aortic stenosis facing noncardiac surgery. Chest. 2005;128:2944–2953. â•‡ 9. Kazmers A, Cerqueira MD, Zierler DE, et al. Perioperative and late outcome in patients with left ventricular ejection fraction of 35% or less who require major vascular surgery. J Vasc Surg. 1988;8(3):307–315. 10. Goldman L, Caldera DL, Nussbaum SR, et al. Multifactorial index of cardiac risk in noncardiac surgical procedures. N Engl J Med. 1977;297:845–850. 11. Detsky AS, Abrams HB, McLaughlin JR, et al. Predicting cardiac complications in patients undergoing noncardiac surgery. J Gen Intern Med. 1986;1:211–219. 12. Eagle KA, Coley CM, Newell JB, et al. Combining clinical and thallium data optimizes preoperative assessment of cardiac risk before major vascular surgery. Ann Intern Med. 1989;110:859–866. 13. American Society of Anesthesiologists. New classification of physical status. Anesthesiology. 1963;24:111. 14. Campeau L. Letter: grading of angina pectoris. Circulation. 1976;54:522–523. 15. Gilbert K, Larocque BJ, Patrick LT. Prospective evaluation of cardiac risk indices for patients undergoing noncardiac surgery. Ann Intern Med. 2000;133:356–359. 16. Lee TH, Marcantonio ER, Mangione CM, et al. Derivation of a simple index for prediction of cardiac risk of major noncardiac surgery. Circulation. 1999;100:1043–1049. 17. Boersma E, Kertai MD, Schouten O, et al. Perioperative cardiovascular mortality in noncardiac surgery: validation of the Lee cardiac risk index. Am J Med. 2005;118:1134–1141. 18. Fleisher LA, Beckman JA, Brown KA, et al. ACC/AHA 2007 guidelines on perioperative cardiovascular evaluation and care for noncardiac surgery: a report of the American College of Cardiology/American Heart Association task force on practice guidelines (writing committee to revise the 2002 guidelines on perioperative cardiovascular evaluation for noncardiac surgery). J Am Coll Cardiol. 2007;50(17):e159–e241. 19. Poldermans D, Fioretti PM, Forster T, et al. Dobutamine stress echocardiography for assessment of perioperative cardiac risk in patients undergoing major vascular surgery. Circulation. 1993;87:1506–1512. 20. Poldermans D, Fioretti PM, Forster T, et al. Dobutamine-atropine stress echocardiography for assessment of perioperative and late cardiac risk in patients undergoing major vascular surgery. Eur J Vasc Surg. 1994;8:286–293. 21. Poldermans D, Arnese M, Fioretti PM, et al. Improved cardiac risk stratification in major vascular surgery with dobutamine-atropine stress echocardiography. J Am Coll Cardiol. 1995;26:648–653.

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22. Ballal RS, Kapadia S, Secknus MA, et al. Prognosis of patients with vascular disease after clinical evaluation and dobutamine stress echocardiography. Am Heart J. 1999;137:469–475. 23. Poldermans D, Boersma E, Bax JJ, et al. The effect of bisoprolol on perioperative mortality and myocardial infarction in high-risk patients undergoing vascular surgery. Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography Study Group. N Engl J Med. 1999;341:1789–1794. 24. Das MK, Pellikka PM, Mahoney DW, et al. Assessment of cardiac risk before nonvascular surgery: dobutamine stress echocardiography in 530 patients. J Am Coll Cardiol. 2000;35:1647–1653. 25. Boersma E, Poldermans D, Bax JJ, et al. Predictors of cardiac events after major vascular surgery: role of clinical characteristics, dobutamine echocardiography, and beta-blocker therapy. JAMA. 2001;285:1865–1873. 26. Karagiannis SE, Elhendy A, Feringa HH, et al. The long prognostic value of wall motion abnormalities during the recovery phase of dobutamine stress echocardiography after receiving acute beta-Â� blockade. Coron Artery Dis. 2007;18:187–192. 27. Boucher CA, Brewster DC, Darling RC, et al. Determination of cardiac risk by dipyridamol-thallium imaging before peripheral vascular surgery. N Engl J Med. 1985;312:389–394. 28. Cutler BS, Leppo JA. Dipyridamole thallium 201 scintigraphy to detect coronary artery disease before abdominal aortic surgery. J Vasc Surg. 1987;5:91–100. 29. Mangano DT, London MJ, Tubau JF, et al. Dipyridamole thallium-201 scintigraphy as a preoperative screening test: a re-examination of its predictive potential. Study of Preoperative Ischemia Research Group Circulation. 1991;84:493–502. 30. Baron JF, Mundler O, Bertrand M, et al. Dipyridamole-thallium scintigraphy and gated radionuclide angiography to assess cardiac risk before abdominal aortic surgery. N Engl J Med. 1994;330:663–669. 31. Etchells E, Meade M, Tomlinson G, Cook D. Semiquantitative dipyridamole myocardial stress perfusion imaging for cardiac risk assessment before noncardiac vascular surgery: a meta-analysis. J Vasc Surg. 2002;36:534–540. 32. Mollet NR, Cademartiri F, van Mieghem CA, et al. High-resolution spiral computed tomography coronary angiography in patients referred for diagnostic conventional coronary angiography. Circulation. 2005;112:2318–2323. 33. Schijuf JD, Pundziute D, Jukema JW, et al. Diagnostic accuracy of 64-slice multislice computed tomography in the non-invasive evaluation of significant coronary artery disease. Am J Cardiol. 2006;98:145–148. 34. Bamberg F, Dannemann N, Shapiro MD, et al. Association between cardiovascular risk profiles and the presence and extent of different types of coronary atherosclerotic plaque as detected by multidetector computed tomography. Arterioscler Thromb Vasc Biol. 2008;28(3):568–574. 35. Rasouli ML, Shavelle DM, French WJ, et al. Assessment of coronary plaque morphology by contrast-enhanced computed tomographic angiography: comparison with intravascular ultrasound. Coron Artery Dis. 2006;17(4):359–364. 36. Malagutti P, Nieman K, Meijeboom WB, et al. Use of 64-slice CT in symptomatic patients after coronary bypass surgery: evaluation of grafts and coronary arteries. Eur Heart J. 2007;28:1879–1885. 37. Soon KH, Kelly AM, Cox N, et al. Non-invasive multislice computed tomography coronary angiography for imaging coronary arteries, stents, and bypass grafts. Intern Med J. 2006;36:43–50. 38. Oncel D, Oncel G, Karaca M. Coronary stent patency and in-stent restenosis: determination with 64-section multidetector CT coronary angiography—initial experience. Radiology. 2007;242:403–409. 39. Cademartiri F, Schujif JD, Pugliese F, et al. Usefulness of 64-slice multislice computed tomography coronary angiography to assess in-stent restenosis. J Am Coll Cardiol. 2007;49:2204–2210. 40. Henneman MM, Schuijf JD, Jukema JW, et al. Assessment of global and regional left ventricular function and volumes with 64-slice MSCT: a comparison with 2D echocardiography. J Nucl Cardiol. 2006;13(4):480–487.

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41. Bellenger NG, Burgess M, Ray SG, et al. Comparison of left ventricular ejection fraction and volumes in heart failure by two-dimensional echocardiography radionuclide ventriculography and cardiovascular magnetic resonance: are they interchangeable? Eur Heart J. 2000;21:1387–1396. 42. Giang TH, Nanz D, Coulden R, et al. Detection of coronary artery disease by magnetic resonance myocardial perfusion imaging with various contrast medium doses: first European multi-centre experience. Eur Heart J. 2004;25:1657–1665. 43. Sakuma H, Suzawa N, Ichikawa Y, et al. Diagnostic accuracy of stress first-pass contrast-enhanced myocardial perfusion MRI compared with stress myocardial perfusion scintigraphy. AJR Am J Roentgenol. 2005;185:95–102. 44. Kim WY, Danias PG, Stuber M, et al. Coronary magnetic resonance angiography for the detection of coronary stenosis. N Engl J Med. 2001;345:1863–1869. 45. Syed MA, Paterson DI, Ingkanisorn WP, et al. Reproducibility and inter-observer variability of dobutamine stress CMR in patients with severe coronary disease: implications for clinical research. J Cardiovasc Magn Reson. 2005;7:763–768. 46. Paetsch I, Jahnke C, Ferrari VA, et al. Determination of interobserver variability for identifying inducible left ventricular wall motion abnormalities during dobutamine stress magnetic resonance imaging. Eur Heart J. 2006;27:1459–1464. 47. Hundley WG, Morgan TM, Neagle CM, et al. Magnetic resonance imaging determination of cardiac prognosis. Circulation. 2002;106(18):2328–2333. 48. Rerkpattanapipat P, Morgan TM, Neagle CM, et al. Assessment of preoperative cardiac risk with magnetic resonance imaging. Am J Cardiol. 2002;90(4):416–419. 49. Poldermans D, Boersma E, Bax JJ, et al. The effect of bisoprolol on perioperative mortality and myocardial infarction in high-risk patients undergoing vascular surgery. Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography Study Group. N Engl J Med. 1999;341:1789–1794. 50. Feringa HH, Bax JJ, Boersma E, et al. High dose of beta-blockers and tight heart rate control reduce myocardial ischemia and troponin T release in vascular surgery patients. Circulation. 2006;114 (suppl 1):I344–I349. 51. Devereaux PJ, Yang H, Yusuf S, et al; for the POISE Study Group. Effects of extended-release metoprolol succinate in patients undergoing non-cardiac surgery (POISE trial): a randomised controlled trial. Lancet. 2008;371(9627):1839–1847. 52. Poldermans D, Bax JJ, Kertai MD, et al. Statins are associated with a reduced incidence of perioperative mortality in patients undergoing major noncardiac vascular surgery. Circulation. 2003;107:1848–1851. 53. Durazzo AE, Machado FS, Ikeoka DT, et al. Reduction in cardiovascular events after vascular surgery with atorvastatin: a randomized trial. J Vasc Surg. 2004;39(5):967–975. 54. Posner KL, van Norman GA, Chan V. Adverse cardiac outcomes after noncardiac surgery in patients with prior percutaneous transluminal coronary angioplasty. Anesth Analg. 1999;89:553–560. 55. Kaluza GL, Joseph J, Lee JR, Raizner AE. Catastrophic outcomes of noncardiac surgery soon after coronary stenting. J Am Coll Cardiol. 2000;35:1288–1294. 56. Wilson SH, Fasseas P, Orford JL, et al. Clinical outcome of patients undergoing non-cardiac surgery in two months following coronary stenting. J Am Coll Cardiol. 2003;42:234–240. 57. McFalls EO,Ward HB, Moritz TE, et al. Coronary artery revascularization before elective major vascular surgery. N Engl J Med. 2004;351:2795–2804. 58. Poldermans D, Schouten O, Vidakovic R, et al; for the Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography Study Group. A clinical randomized trial to evaluate the safety of a noninvasive approach in high-risk patients undergoing major vascular surgery: the DECREASE-V Pilot Study. J Am Coll Cardiol. 2007;49:1763–1769.

15

Congenital Heart Disease

MA RK A . FOGEL

Since its inception, cardiac imaging has changed the face of the way cardiology has been practiced and has revolutionized medical and surgical management of nearly all lesions. Within cardiac imaging, the patient with congenital heart disease (CHD) presents one of the most challenging aspects to the discipline. Besides distorted anatomy and complex physiology, visualizing cardiovascular structures and assessing ventricular function and blood flow in infants and children present a technical challenge with their small structures and high heart rates relative to adults. To understand CHD is to first define it, which was done by Mitchell et al. in 1971 as a “gross structural abnormality of the heart or intrathoracic great vessels that is actually or potentially of functional significance.” It is easiest to divide CHD into simple and complex lesions. Simple is defined as isolated structural abnormalities within CHD without conotruncal abnormalities. As surprising as it might sound, CHD is fairly common, and simple CHD makes up the vast majority of these. Hoffman and Kaplan [1] surveyed the literature in 2002 and found the incidence of bicuspid aortic valve to be approximately 13â•›556 per million live births which is more than all other forms of CHD combined. Of the top 9 most frequent lesions reported, 7 would be considered simple (ventricular and atrial septal defects [ASD], bicuspid aortic valve, pulmonary and aortic stenosis, patent ductus arteriosus, and coarctation). Combined, these lesions make up approximately 88% of all CHD. Complex CHD, on the other hand, make up only a small portion of CHD and are rare in the population; these diseases, however, constitute an inordinate amount of the physician’s time. If CHD is one of the most difficult diseases in cardiac imaging, complex CHD is one of the most challenging issues that the health care provider, who takes care of the pediatric patient with cardiac lesions, has to face. Taken as a group, the incidence of this set of lesions (moderate to severe forms of CHD), reported by Hoffman and Kaplan, was 6/1000 live births; this number increases to 19/1000 live births if potentially serious bicuspid aortic valves are included. Note that all forms of CHD represent 75/1000 live births including such lesions as tiny muscular VSDs. Using 238

cardiac death in early infancy, cardiac surgery, or the need for cardiac catheterization as a measure of disease severity, the New England Infant Cardiac Program [2] reported that 3/1000 live births fell into these categories. This number rose to 5/1000 live births when considering children who will need some kind of specialized facilities during their lifetime. Patients with CHD are living longer, in part due to improvements in diagnosis and management along with a greater understanding of anatomy and physiology [3]. Thus, there is an increasing number of patients with CHD coming for medical attention by adult cardiologists and internists. In 2000, there was an estimated 1 million adults with CHD; this is anticipated to grow to 1.4 million by 2020. This chapter first addresses some general basics of multimodality imaging in CHD, followed by examples of specific lesions following the classification scheme delineated above. Two in-depth examples will be demonstrated in each, focusing mostly on the role of noninvasive imaging. Since imaging in CHD borrows from imaging in adult cardiovascular disease, a detailed explanation of the imaging modality will not be presented but rather how the imaging modality is tailored to the CHD population.

jâ•… IMA GING PRINCIPLES IN CHD The noninvasive imaging modalities used in CHD include chest x-ray (CXR), echocardiography, cardiac magnetic resonance (CMR), and to a very limited extent, computed tomography (CT) and radionuclide angiography. Invasive cardiac angiography is still utilized for diagnostic purposes; however, it has been mostly supplanted by noninvasive techniques. Most cardiac catheterization procedures today are interventional or therapeutic procedures (eg, coil or stent placement). Nevertheless, angiography is still used at some institutions to diagnose such diseases as anomalous coronary arteries or to identify aortopulmonary collaterals. Chest X-ray The CXR formerly played a very important role in CHD; the patient would be placed in various positions for a cardiac series to diagnose lesions. Shapes of the heart were

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used to diagnose CHD such as the egg-on-a-string shape for classic transposition of the great arteries (TGA), the tipped up apex or coeur-en-sabot appearance of tetralogy of Fallot or the box-shaped heart of partial absence of the pericardium. Extracardiac structures and signs such as the scimitar sign in scimitar syndrome (partial anomalous right pulmonary venous connection below the diaphragm with right lung and generally right pulmonary artery hypoplasia) were often used. CXRs still play an important, yet downsized role in CHD despite being considered low tech. It is usually the first test obtained and can clue the imager to what may lie in store during subsequent higher tech scans. CXR can also be utilized, for example, in patients with heterotaxy syndrome to sort out abdominal and thoracic situs; dextrocardia will be fairly obvious. A right aortic arch, suggested by leftward deviation of the trachea, can suggest the presence of a vascular ring or more Â�complex heart disease associated with right aortic arches (eg, tetralogy of Fallot, truncus arteriosus). Cardiomegaly can be a tip off to CHD, pericardial effusion, or heart failure in a child with myocarditis, dilated cardiomyopathy, or a VSD. Pulmonary vascularity can be utilized to determine overcirculation and indeed, a classification of CHD has been developed depending upon whether there is increased or decreased pulmonary vascularity on CXR. Finally, it is extensively used in the postoperative or postinterventional period to determine, for example, placement of an endotracheal tube, position of devices such as stents or coils and the presence of pleural effusions. Echocardiography Echocardiography is, by far, the mainstay of anatomic and physiologic diagnosis allowing for detailed assessment of the geometry and architecture of cardiovascular structures, assessment of dynamic movement of components of these structures, and evaluation of blood flow. The application of echocardiography to CHD has been extremely useful in revealing the complexities of heart disease in infants and children for a number of reasons. It uses ultrasound and not ionizing radiation, which makes it a much safer tool in this very radiosensitive age group. It has relatively high spatial resolution demanded to evaluate the very small structures of the infant, and even the fetal cardiovascular system as well as the high temporal resolution also demanded by the high heart rates found in this age group. This allows for reliable tracking of the dynamic movement of tiny structures over time. The equipment is mobile, which allows for use at the patient bedside and therefore can be used for serial evaluations with minimal disturbance to the patient. The above benefits along with the familiarity of echocardiography to the health care provider and its relatively lower cost have made echocardiography ubiquitous in the clinical management of CHD; it has been a major contributor to improved clinical outcomes over the past 30 years.

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There are a few limitations that exist in echocardiography as applicable to CHD. Ultrasound energy cannot travel through bone or lung and therefore, the echocardiographer must use windows of muscle or fluid to visualize cardiovascular structures; some children have poor acoustic windows or not enough muscle in between bones to utilize the ultrasound beam properly and the resulting images are poor as well. In addition, the field of view of echocardiography is much more limited than other imaging modalities such as CMR; this is important in CHD, where abnormal connections of different cardiovascular structures, the presence or absence of these structures along with their relationship to the extracardiac thoracic, and abdominal structures are important for precise delineation of disease states. This is exemplified by heterotaxy in which the inferior vena cava may be interrupted, 2 leftsided bronchi may be present, total anomalous pulmonary venous connection below the diaphragm may be present, or the abdominal contents may be on the opposite side. These can all occur simultaneously and thus a wide field of view of all structures is desirable. Many devices or artificial valves cause artifacts that can also degrade image quality. The technique is inherently a 2-dimensional (2D) technique despite technical advances made to morph it into a 3D one. With the bizarre shapes of ventricles that exist in CHD, an inherently 3D technique would be more useful. Image processing is a function of the returning ultrasound signal, so that the physical properties of scatter, penetration, absorption, and reflection and so on play a role. In addition, there is signal degradation with increasing distance through which the ultrasound energy must travel. As children grow, its utility becomes much more limited because the distance the beam must travel is longer, along with the increasingly poor acoustic windows of adulthood. A major difference between adult and pediatric echocardiography are the echocardiographic windows used and how the exam is performed. Pediatric echocardiographers rely heavily on the subcostal window from the liver, as it is the one with the widest field of view, which is especially important in patients with unknown diseases. Other windows such as the apical, parasternal, and suprasternal notch views are also used but not to the same extent. In addition, echocardiography in CHD also relies heavily on sweeps within a given window; that is, in a window, the transducer is tilted different ways to cover as much anatomic ground as possible, making up for the limited field of view in any given image. For example, the subcostal window has the following sweeps/views: (1) frontal sweep, where the beam is in a slightly off-axis transverse view and is tilted superiorly until it is nearly coronal; (2) sagittal, sweep where the beam is in a sagittal view and is tilted right-left; (3) left anterior oblique (LAO), sweep where the beam is in the catheterization laboratory equivalent of an LAO view that is half way between a frontal and sagittal view and the

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sweep progresses from inferior and rightward to superior and leftward; and (4) right anterior oblique (RAO) view, similar to an RAO view in the catheterization laboratory. Finally, because any configuration of cardiovascular structures is possible, echocardiography in CHD is performed in the anatomically correct position—inferior is at the bottom of the image, superior is at the top of the image, the patient’s right is on the left hand side of the image, and the patient’s left is on the right side of the image. Doppler blood flow assessment is used similar to adult cardiovascular disease. Color flow mapping is used in CHD to assess for valve stenosis (eg, stenotic bicuspid aortic valve) or regurgitation (eg, tetralogy of Fallot after repair with a transannular patch), vessel stenosis (eg, branch pulmonary artery stenosis in TGA after repair), and septal communications (eg, atrial septal or VSDs) to name a few of the many applications. Doppler spectral recording is used to determine, among other applications, turbulent flow and velocities to measure gradients across stenoses (eg, coarctation of the aorta) or estimate chamber pressures (eg, right ventricular pressure estimate in patients with pulmonary stenosis by utilizing the tricuspid regurgitant jet) using the Bernoulli equation or calculating the myocardial performance (Tei) index (eg, to assess ventricular performance in patients with corrected transposition). Doppler tissue imaging, strain rate imaging, and speckle tracking are all finding roles in CHD as in adult cardiovascular disease. Other echocardiographic techniques used in CHD have special applications. Transesophageal echocardiography is used commonly in the operating room to assess surgical repair (eg, residual VSDs after closure or left atrioventricular valve insufficiency after repair of complete common atrioventricular canal), in the catheterization lab to aid in device closure of ASD, or at the bedside to guide the interventionalist for balloon atrial septostomy in patients with TGA. Intracardiac echocardiography has also played a role in interventional cardiology (eg, device closure of septal defects in the catheterization laboratory). Cardiac Magnetic Resonance CMR has been utilized for over 25 years in cardiac imaging and is an established technique in the care of infants, children, adolescents, and adults with CHD. It is becoming more widely used in institutions all over the globe. CMR is generally used in conjunction with other imaging modalities (eg, echocardiography and angiography); however, in some areas such as vascular rings [4], ventricular function, and blood flow, it has become the gold standard. CMR in CHD is a one-stop shop with multiple techniques such as bright- and dark-blood imaging and gadolinium-enhanced sequences to visualize anatomy. Cine, including real-time techniques, myocardial tagging, and phase-encoded velocity mapping can accurately assess ventricular function and

Multimodality Imaging in Cardiovascular Medicine

blood flow in 3 dimensions. Navigators with T2-prepared steady-state free precession with fat saturation can visualize the coronary arteries, while tissue characterization techniques can image myocardial scarring and detect the amount of iron overload in the heart. There are a number of special contributions that make CMR applicable to CHD. Anatomically, CMR can visualize the great vessels and their relationship with each other and the trachea much simpler than other imaging modalities. As mentioned above, this has made CMR the gold standard for the assessment of vascular rings (eg, double aortic arch, right aortic with a diverticulum of Komerrel, and an aberrant left subclavian artery). The acquisition of a 3D data set that can be manipulated in multiple ways to visualize the salient points of the anatomy, independent of acoustic windows and without ionizing radiation, is an extremely useful clinical tool. Because of its inherent 3D nature, the relationship of the atria and ventricles to each other and the great vessels contributes to understanding complex CHD such as in heterotaxy, double-outlet right ventricle (RV), and corrected TGA (ie, {S,L,L}). Gadolinium-based CMR sequences, besides creating 3D models of the cardiovascular system, can identify very small vessels (such as collaterals in patients with coarctation or tetralogy of Fallot with pulmonary atresia). Coronary artery imaging is not just for adult disease, and the ability of CMR to image congenital coronary lesions such as anomalous left coronary artery from the pulmonary artery, acquired coronary disease such as aneurysms in Kawasaki’s disease, and surgically manipulated coronaries such as in TGA after arterial switch or the Ross procedure is very important. Another major strength of CMR is the ability to assess ventricular function and physiology in CHD; it is considered the gold standard in this area in many applications. Ventricular volumes and ejection-phase parameters of function can be very precisely calculated by CMR using cine techniques independent of geometric assumptions [5], which is clinically important in cases of CHD with ventricular volume overload lesion such as native VSDs, aortic insufficiency, or repaired tetralogy of Fallot in which pulmonary insufficiency can cause significant dilatation of the RV. In nearly all applications, these images are created from multiple, sometimes hundreds of heartbeats averaged together, which better reflects the true nature of ventricular function (as opposed to instantaneous imaging such as echocardiography or cardiac angiography). This average is embedded in the image, whereas the echocardiographer needs to evaluate many heartbeats and average these in their mind to come to a conclusion. Phase-encoded velocity mapping is utilized to measure flow (averaged over many heartbeats), which is advantageous in CHD. Shunt flow (Qp/Qs) [6] in simple lesions such as ASD or regurgitant fractions in lesions with valve insufficiency (eg, pulmonary insufficiency after balloon valvuloplasty for pulmonary stenosis) can

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be calculated in this manner. These measurements are not dependent upon the assessment of oxygen consumption (as in cardiac catheterization), do not rely on the geometric shape of the vessel as in echocardiography, and are typically checked for internal consistency. For example, the regurgitant volume in the pulmonary artery in repaired tetralogy of Fallot must be nearly equal to the difference in stroke volumes of both ventricles, assuming no other valvular insufficiency or intracardiac shunts. Flows to right and left lungs by utilizing velocity mapping in both branch pulmonary arteries must sum to the flow in the main pulmonary artery. Time-resolved 3D gadolinium sequences [7] are a hybrid of both anatomic and physiologic information. They can track the flow of blood from the venous side to the arterial side of the circulation (yielding images similar to cardiac angiography), and each phase can be created into a 3D volume-rendered image. They can provide physiologic information regarding shunts; for example, in the case of a superior vena cava overriding the atrial septum in a sinus venosus ASD, both right and left atria would become signal intense simultaneously. In patients with corrected transposition (TGA {S,L,L}) who are after a double switch (both atrial and arterial inversion procedures—Senning and arterial switch), the left side of the heart would demonstrate increased signal first with flow into the pulmonary arteries, followed by the right side of the heart demonstrating increased signal with flow into the aorta. Other CMR techniques are useful in the assessment of ventricular function and physiology in CHD. Myocardial tagging [8], a unique ability of CMR to noninvasively label tissue, is useful in identifying regional ventricular wall dysfunction, which may be present in patients with cardiomyopathy or arrhythmogenic right ventricular dysplasia. It can be used to calculate strains and wall motion in 3 dimensions; regional wall function differences have been noted in single-ventricle patients throughout staged surgical reconstruction. Myocardial perfusion imaging, performed with and without adenosine by injecting gadolinium and observing the increased signal intensity in the myocardium, can be used for the assessment of diseases such as hypoplastic left heart syndrome (HLHS) or other single-ventricle complexes, where coronary artery disease may be present. Patients with surgically manipulated coronary arteries such as TGA after arterial switch or the Ross procedure mentioned above can benefit from this form of imaging. Tissue characterization by CMR can aid in the diagnosis of cardiac tumors (eg, fibroid tumors, hemangiomas) and can detect areas of myocardial scar tissue by delayed contrast enhancement that may be present in, for example, anomalous left coronary artery from the pulmonary artery or tetralogy of Fallot. T2* techniques can be used to determine iron overload in patients with thalassemia or sickle cell disease, and chelation therapy is manipulated based on these measurements.

Computed Tomography CT is being increasingly utilized in adult cardiac imaging. However, it has little role in CHD because of its use of ionizing radiation (see next paragraph), exposure to iodinated contrast, and the presence of alternative imaging such as CMR. It should be used only after CMR has been attempted. CT still has higher spatial resolution than CMR and can be used to detect degrees of coronary stenoses that CMR may not be able to detect (eg, after Kawasaki’s disease). CT should not be used for prettier images because of its higher spatial resolution when CMR can provide the diagnosis with lower spatial resolution (eg, anomalous origins of the coronary arteries). This imaging modality, however, can provide well-detailed anatomic delineation of CHD and limited spatial and temporal resolution of function. Assessment of myocardial scarring and strain imaging have been studied, but these expose the patient to even more radiation. A Note on Radiation in Cardiac Imaging in CHD A major concern in the pediatric population is the use of ionizing radiation-based cardiac imaging procedures, because the major resultant cause of morbidity and mortality, neoplastic disease, is usually manifested years after the test and long after the clinician ordering the test may have retired. The long time to manifest this side effect, despite the severity of the consequences, is the major reason why it is so difficult for clinicians and patients to pay close attention to it. There are unique considerations in children and young adults that need to be considered as: (1) children are considerably more radiosensitive than adults as demonstrated in numerous epidemiologic studies, (2) children have a longer life expectancy than adults, resulting in a long window for expressing radiation damage and neoplastic disease, and (3) children usually receive a higher dose than necessary when adult CT settings are used. Because of all this, the risk for developing a radiation-related cancer is many times higher for patients in the pediatric age range as opposed to adults. As such, official statements from various international and national organizations state that radiation considerations need to play an important role in determining which imaging modality should be used. For example, a statement published in the European Heart Journal in 2004 [9], The European Society of Cardiology, prefers CMR because “the lack of ionizing radiation is an important consideration when performing sequential studies in children and young adults.” A 2008 statement from the American Heart Association on noninvasive coronary imaging states that, “anomalous coronary artery evaluation can be performed by either CTA or MRA; radiation-protection concerns indicate that MRA is preferred when it is available. (Class IIa, level of evidence B)” [10].

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There are some who state that radiation doses can be minimized and children will be safe. The scientists at the National Cancer Institute state it succinctly and clearly on their Web site: “Major national and international organizations responsible for evaluating radiation risks agree there probably is no low-dose radiation ‘threshold’ for inducing cancers, that is, no amount of radiation should be considered absolutely safe” [11]. In addition, radiation exposure, even if minimized in an individual examination, is especially important in CHD patients who generally undergo numerous cardiac catheterizations, nuclear scans, and occasionally CT scans during their lifetime. The cumulative increased risk from these multiple exposures to radiation-based techniques put these children at an unusually high risk. Of course, any risk must be weighed against the benefit a patient may receive and the risk of not obtaining data needed for care. Imaging techniques such as CT scanning, radionuclide angiography, and diagnostic cardiac angiography should be used only when (1) CMR and echocardiography cannot obtain the information; (2) there is a contraindication to CMR; (3) increased spatial resolution is needed, which CMR or echo cannot provide (eg, subtle coronary artery stenosis after coronary manipulation such as in the Ross procedure); or (4) CMR is unavailable. If alternatives to radiation-based imaging modalities exist, the physician is ethically obligated to use these first before exposing the patient to radiation.

Multimodality Imaging in Cardiovascular Medicine

F ig u re 1 5 . 1 â•…Echocardiographic subcostal left anterior oblique view of a patent foramen ovale with color flow mapping demonstrating shunting left to right. The flap valve is clearly seen.

jâ•… SIM PLE CHD Isolated Atrial Septal Defects The anatomy of the atrial septum is complex and it is important to understand while imaging communications between right atrium (RA) and left atrium (LA). It is composed of a number of components that determine what kind of ASD is present. Septum primum, septum secundum, and the atrioventricular canal septum all coalesce to create the wall between RA and LA, with a flap valve (which eventually closes in most people) created when septum primum meets septum secundum. A patent foramen ovale occurs when this flap valve remains patent (Figure 15.1). An ostium primum ASD occurs when there is a failure of the atrioventricular canal septum to form, whereas a secundum ASD (Figures 15.2 and 15.3) occurs as a defect in septum primum. A coronal sinus septal defect is caused by the absence of a part of the roof of the coronary sinus, such that blood from the LA can shunt across the defect, through the os of the coronary sinus into the RA. Finally, a sinus venosus ASD (Figure 15.4) occurs when there is a defect in the atrial wall between superior vena cava and right upper pulmonary vein (superior vena cava type) as well as inferior vena cava and right lower pulmonary vein

F ig u re 1 5 . 2 â•…Echocardiographic subcostal left anterior oblique view of a secundum atrial septal defect shunting left to right.

(inferior vena cava type). Besides having created a potential for stroke with paradoxical emboli from right to left flow, the presence of an ASD can eventually cause pulmonary hypertension or ventricular volume overload. Echocardiography is generally the first imaging study when these lesions present and is typically excellent for anatomic and physiologic delineation (Figures 15.1–15.3). The 2 key views to visualize the defects are subcostal and parasternal short-axis views. Secundum and priumum ASDs are best seen in the subcostal LAO view, while sinus venosus ASDs are best seen in the subscostal sagittal view. It is important to delineate the right pulmonary veins in

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Congenital Heart Disease2 4 3

F ig u re 1 5 . 3 â•… 2-dimensional echocardiographic subcostal left anterior

oblique view of a secundum atrial septal defect; the asterisk is placed wherein the deficiency of the atrial septum is seen.

sinus venosus ASDs so that the surgeon knows where they are prior to operating to understand whether they need to be baffled or whether a Warden procedure is necessary. The apical view should not be relied on to visualize an ASD since the atrial septum is parallel to the beam and false dropout may occur, although left to right shunting on color flow mapping may suggest that this defect is present. Color Doppler is important to determine the direction of flow and can be useful to detect very small defects. If the diagnosis remains questionable after performing 2D echocardiography and color flow mapping, contrast echocardiography or a bubble study (eg, injection of agitated saline) may be performed to detect any right to left flow in the absence of pulmonary arteriovenous malformations. A Valsalva maneuver may be performed to aid this in the contrast study. Transesophageal echocardiography is the gold standard of echocardiography for delineating these defects because of its clarity owing to the proximity of the transducer to the lesion. With the advent of transcatheter devices to close ASDs, it is important for the echocardiographer to delineate not only how large the ASD is but also the rims around the defect needed to anchor the device. In general, these patients are referred for CMR to assess the Qp/Qs [4], to quantitate right ventricular volume overload and to identify pulmonary veins that may not have been identified on echocardiography. A general exception to this is the older patient or adult who has poor transthoracic windows when there is an index of suspicion that these defects exist. CMR can visualize the defects using a number of techniques (Figure 15.4), including double-inversion dark-blood imaging, bright-blood

B F ig u re 1 5 . 4 â•… (A) Cine cardiac magnetic resonance sagittal view

of a sinus venosus atrial septal defect of the superior vena cava type; the asterisk is placed wherein the deficieny of the atrial septum is seen. (B) In-plane phase-encoded velocity mapping of the exact image in (A) demonstrating left to right flow; black encodes blood flow anteriorly from left to right atrium.

imaging with or without blood tagging using a saturation band [12,13], or with in-plane phase-encoded velocity mapping. CMR has even been used to size ASDs as, for example, Beerbaum et al showed with phase-encoded velocity mapping. They studied 65 children with CMR and determined ASD size and rims and detected associated venous anomalies when transthoracic echocardiography results were inconclusive [14]. Axial bright-blood images can nearly always delineate pulmonary venous connections and drainage. Since Qp/Qs is the other most important piece of information obtained at CMR, phase-encoded velocity mapping is performed following this set of images. Flow information is obtained

2 4 4Multimodality Imaging in Cardiovascular Medicine

across the cross-sectional area of ascending aorta, main pulmonary artery, and both branch pulmonary arteries (the latter is used as an internal check of the data). After the Qp/Qs is measured via velocity mapping, cine CMR can be used to obtain left and right ventricular volumes to document the volume overload physiology. This is also used as an internal check for velocity mapping data as the cardiac outputs should match and the difference in stroke volumes in the absence of atrioventricular valve regurgitation should also be the Qp/Qs. Simple Coarctation of the Aorta

A

B

C 1 5 . 5 â•… (A) 2-dimensional echocardiographic suprasternal notch candy cane view of a coarctation of the aorta. (B) Color Doppler flow imaging in the same plane as in (A) demonstrating increased velocity and aliasing as the level of the coarctation. (C) Continuous-wave Doppler spectral recording displaying a classic coarctation pattern with diastolic runoff in the same patient; peak velocity was measured at 3.5/s.

F ig u re

This is one of the most common congenital vascular lesions and in isolation, can occur anywhere in the descending aorta but most commonly occurs in the proximal descending aorta near the insertion of the ligamentum arteriosum. It is commonly associated with bicuspid aortic valve and can also be associated with collaterals to bypass the obstruction. The degree of obstruction can, at first pass, be assessed by blood pressure differences between arms and legs. However, factors such as collateral flow, poor cardiac output, and anatomically where the narrowing is located can falsely lower the assessment of the severity of the lesion. Left ventricular hypertrophy may occur. There are other associations with complex CHD that will not be addressed here. In older patients, the CXR, can show rib notching. Echocardiography is generally obtained as the first study and in younger children, it is usually successful at delineating the degree of narrowing by 2D imaging in the candy cane view of the aorta from the suprasternal notch window (Figure 15.5), which is an off-axis sagittal view. This view can also assess the degree of post-stenotic dilation and ascending aortic enlargement if a bicuspid valve is present. It is also important for the imager to determine whether the aortic arch is right or left sided, as these lesions are generally repaired via a thoracotomy; this is done by echocardiography utilizing a frontal sweep (essentially a coronal series of images) from the suprasternal notch window. The sidedness of the arch is considered contralateral to the course of the first branch, although this general rule of thumb has a few exceptions to it (eg, a right aortic arch with an aberrant left innominate artery). Color Doppler imaging will almost always demonstrate aliasing of flow at the level of the narrowing (Figure 15.5B). Pulse-wave and continuous-wave Doppler techniques (Figure 15.5C) are then used to estimate the gradient across the narrowing using the Bernoulli equation; it is important to use both the proximal (by pulse-wave Doppler) and distal velocities (by continuous-wave Doppler) in this formula since the proximal velocity may not be negligible. Echocardiography is also utilized to determine if the patient has a bicuspid aortic valve as well as the degree of left ventricular hypertrophy from the parasternal short-axis view. A notable

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A F ig U re 1 5 . 7 â•… In-plane phase-encoded velocity mapping by cardiac magnetic resonance in the candy cane view demonstrating acceleration of flow (black jet) at the level of a coarctation. Flow is encoded white superiorly and black inferiorly.

B F ig U re 1 5 . 6 â•… 3-dimensional reconstruction from gadolinium-enhanced

cardiac magnetic resonances. (A) Aorta viewed from posterior demonstrating a coarctation. The patient also has a retroaortic innominate vein. (B) Older patient with multiple collaterals which bypass the coarctation (arrow).

limitation to echocardiography is that some regions of the aorta in the thorax may not be visualized well if at all. If there is a low coarctation inferiorly in the thorax, a false negative may result. Coarctation of the aorta, both preoperative and postoperative, has been an extremely common referral to CMR for many years (Figures 15.6 and 15.7) [15]. Imaging begins with static steady-state free precession and/or doubleinversion dark-blood imaging in the candy cane view of the aorta. It is performed by aligning a plane on the axial images between ascending and descending aorta at the level of the pulmonary bifurcation in an off-axis sagittal view. Because the aorta may be tortuous in some lesions, it may not lend itself to display in a single plane. What may appear to be a coarctation in an ideal candy cane view may actually just be this ideal plane missing a section of the vessel. Static images are performed on either side of the

candy cane to ensure proper diagnosis and the diameter of the coarctation site can then be measured. To obviate this problem, 3D gadolinium-enhanced imaging is useful for demonstrating the coarctation as the curves of the aorta will not go out of the 3D slab (Figure 15.6). In addition, 3D gadolinium imaging is extremely useful in delineating all the collaterals around the coarctation site (Figure 15.6). Utilizing the stack of axial images or the 3D gadolinium images, the sidedness of the arch is easily visualized and the location of the coarctation clearly defined. The entire thoracic and abdominal aorta can be visualized well with CMR, and false-negative results are usually near zero. Anatomically, CMR is also indicated for evaluation of aneurysm formation, restenosis, arch hypoplasia, or pseudoaneurysm after surgical repair. Cine CMR is performed in the candy cane view to image the signal void due to turbulence across the coarctation site. Other views obtained via cine CMR is the 4-chamber view and a stack of left ventricular short-axis slices that can quantify left ventricular hypertrophy and function, as well as assess for mitral insufficiency. Cine CMR can be used to determine if a bicuspid aortic valve is present, typically by using a gradient echo sequence with a high flip angle. Through-plane velocity mapping is performed in the ascending aorta and main pulmonary artery to measure the cardiac index. CMR has been utilized to also measure the volume of collateral flow [16] (Figure 15.6) by placing a through-plane velocity map at the level of the proximal descending aorta and the aorta at the level of the diaphragm. In normal individuals, the aortic flow at the diaphragm should be approximately the same or slightly lower than the flow in the proximal descending aorta

2 4 6Multimodality Imaging in Cardiovascular Medicine

(flow in the intercostal arteries makes up the difference). In coarctation of the aorta, because collateral flow can develop around the coarctation site, flow at the level of the diaphragm is actually greater than flow in the proximal descending aorta, since flow in the ascending aorta and transverse arch skips the coarctation site and winds up in the aorta near the diaphragm. The gradient across the coarctation can also be measured by CMR using inplane (Figure 15.7) and through-plane velocity mapping. The slice thickness with in-plane velocity mapping should be as thin as possible without sacrificing the signal-to-noise ratio to unacceptable levels since partial volume effects will cause an error in the measurement. Through-plane velocity mapping with a low echo time and a high velocity encoding at what appears to be the highest velocity on in-plane velocity mapping appears to be the most accurate way to measure this. F ig u re 1 5 . 8 â•…Echocardiographic subcostal frontal view of a patient

with transposition of the great arteries. Note how the pulmonary artery arises from the left ventricle.

jâ•… COMPLEX CHD Transposition of the Great Arteries (Figures 15.8–15.11) TGA is actually a group of lesions that all have in common ventriculo-arterial discordance, with the aorta arising from the RV and the main pulmonary artery arising from the left ventricle (LV). This results in the systemic and pulmonary circulations being in parallel with each other with limited mixing of oxygenated and deoxygenated blood (at the atrial level). The classic TGA is usually referred to as d-TGA or TGA {S,D,D}; in general the aortic annulus is anterior and to the right of the pulmonary annulus, although it can be posterior as well in rarer cases. Occasionally, the conotruncus is rotated in such a way as to have the aortic annulus anterior and to the left of the pulmonary valve called TGA {S,D,L}. When the LV is right sided and the RV is left sided, the great arteries can have the arrangement of the aortic annulus anterior and to the left of the pulmonary valve as well and this is the so-called corrected transposition or l-TGA or TGA {S,L,L}. TGA can have multiple associated anomalies such as VSD, patent ductus arteriosus (these 2 lesions being the most common outside of an ASD), pulmonic stenosis (PS), aortic stenosis with a malalignment VSD, and aortic arch hypoplasia or tricuspid atresia. Repair of classic TGA has gone through an evolution from the Baffes procedure (inferior vena cava anastamosis to the LA and right pulmonary vein anastamosis to the RA) to the atrial inversion procedure (baffling caval flow to the mitral valve and pulmonary venous flow to the tricuspid valve using the Senning [17] or Mustard [18] procedure, Figure 15.11) to the arterial switch operation with the Le Compte maneuver in use today (translocating the aorta and coronaries over the pulmonary valve

F ig u re 1 5 . 9 â•… 3-dimensional reconstruction from gadolinium cardiac

magnetic resonance of transposition of the great arteries after arterial switch; note how the pulmonary arteries drape over the ascending aorta (Le Compte maneuver).

and the pulmonary artery over the aortic valve, with draping of the branch pulmonary arteries over the ascending aorta, Figure 15.9). TGA with a VSD and PS is classically repaired by the Rastelli operation with baffling of the VSD from the LV to the aorta and placing a RV to pulmonary artery conduit. CXR, as noted above, classically demonstrates an egg-on-a-string shape to the heart and depending upon whether there is PS, may show increased or decreased pulmonary vascular markings. The mainstay of imaging for unrepaired TGA, however, is echocardiography, where the initial subcostal view in the frontal sweep can cinch the diagnosis of simple TGA (Figure 15.8), as visualizing

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F ig u re 1 5 . 1 1 â•… Cine cardiac magnetic resonance of the 4-chamber

F ig u re 1 5 . 1 0 â•… Cardiac magnetic resonance of the coronaries in

transposition of the great arteries after arterial switch; the right and left coronaries bifurcate from a single coronary (arrow) and the circumflex coronary courses retroaortic.

the great vessel from the LV bifurcating into the right and left pulmonary arteries in this view is a classic finding. The subcostal LAO view is used to assess the atrial septum since an ASD is extremely important for mixing blood between the 2 circulations. Beside the status of the ASD, a complete echocardiogram should focus on delineating the conotruncal anatomy from multiple views (eg, side by side great arteries which would make a Le Compte maneuver undesirable, aortic annulus anterior or posterior, etc), as well as the presence or absence along with size and direction of shunting of a patent ductus arteriosus from a high parasternal view, the presence or absence along with size and type of VSD, the presence or absence of aortic stenosis or PS (from all acoustic windows), and the status of the aortic arch (sidedness, coarctation, hypoplasia, interruption, etc). Defining the coronary artery origins and proximal courses may be possible as well. For unstable patients, a limited echocardiogram will be performed to confirm the diagnosis of TGA and to evaluate the atrial septum to determine whether a restrictive ASD is present. It is fairly common now to utilize transesophageal echocardiography to guide the interventionalist at the bedside to perform a balloon atrial septostomy and to assess the result of the intervention afterwards. CMR generally plays a limited role in the initial management of simple TGA before surgery and is usually used when there are any residual questions after complete echocardiography. It may be useful in some situations in which the coronary anatomy is unusual (Figure 15.10) and needs to be better evaluated prior to arterial switch procedure, if there is a question about the pulmonary arteries or the aortic arch anatomy. Nevertheless, it can unquestionably diagnose infants and children with TGA [19–21]. CMR plays a more extensive and important role in the postoperative management of TGA. In the standard treatment for TGA,

view in transposition of the great arteries after Senning; the right ventricle is very dilated. Both pulmonary and distal systemic venous pathways are easily visualized.

that is, the arterial switch (Jatene procedure) with the Le Compte maneuver (Figure 15.9), several problems can arise which CMR is well suited to investigate. Supravalvar stenosis can occur at either anastomotic site; however, it is more common to find supravalvar neo-PS and dilation of the neoaortic root. 3D gadolinium sequences, cine and phase-encoded velocity mapping can be used effectively to define regions of stenosis and quantify the degree of flow acceleration. In addition, unilateral or occasionally bilateral branch pulmonary artery stenosis may develop as these vessels are stretched after the Le Compte maneuver and this post-operative sequelae can also be easily imaged with the above techniques. Insufficiency of either semilunar valve can result from distortion during surgery, and throughplane velocity mapping can be used to precisely quantify the degree of insufficiency of the valves. As a complementary technique, short-axis cine volume sets will quantify the ventricular size, ejection, and wall motion abnormalities in order to screen for the effects of valve regurgitation or coronary abnormalities. Cine, 3D gadolinium imaging, and velocity mapping can be used to assess left ventricular outflow tract obstruction, the status of the RV to pulmonary artery conduit, and for residual VSD in patients with TGA, a VSD, and PS after a Rastelli procedure. Wholeheart T2-prepared steady-state free precession imaging using a navigator technique (Figure 15.10) can be used to evaluate for ostial stenosis of the transferred coronaries and the absence of a coronary or kinks in the course of the coronary arteries [22]. As a one-stop shop, CMR can be used to evaluate myocardial perfusion defects, performed at rest and during adenosine administration, which may be caused by coronary stenosis. Adenosine administration causes coronary vasodilation and accentuates perfusion abnormalities by stealing flow from regions of marginal coronary perfusion. With delayed contrast enhancement imaging, CMR can identify areas of myocardial scar tissue,

2 4 8Multimodality Imaging in Cardiovascular Medicine

which again may be the result of coronary stenosis or the effects of surgery with deep hypothermic circulatory arrest. Older patients with TGA may have had an atrial inversion or switch (either a Mustard or Senning operation, Figure 15.11) in which the pulmonary venous return is Â�baffled to the RV and the systemic veins to the LV. The RV is the systemic ventricle and is subject to dilation and failure, usually starting in the third and fourth decade of life. In addition, because of right ventricular geometry, it is not uncommon for these patients to develop left ventricular dynamic outflow tract obstruction. CMR, with the capability of accurately measuring right ventricular volume, mass and cardiac output by cine and phase-encoded velocity mapping plays a key role in monitoring biventricular function in these patients and is a common indication [23]. The wide field of view allows for easy visualization of the left ventricular outflow tract and possible obstruction by cine and phase-encoded velocity mapping. Myocardial scarring utilizing delayed contrast-enhanced sequences can be ascertained and can aid in determining therapy. In a small study, myocardial scarring correlated with arrhythmias, age, lower right ventricular ejection fraction, and clinical deterioration [24]. In the Senning and Mustard procedures, both these types of baffles are a sideways Y configuration with an upper limb from the superior vena cava and a lower limb from the inferior vena cava. The upper limb especially is subject to obstruction and narrowing. Echocardiography is usually fairly poor at delineating these limbs, whereas with CMR, the entire length of the systemic venous pathway including both limbs, are easily seen. Baffle leaks and turbulent jets through obstructed pathways can be visualized and measured by cine and phase-encoded velocity mapping. MRI plays a key role in evaluating ventricular function, perfusion, and viability of the systemic RV as well as assessing the baffle for stenosis or leaks.

Functional Single Ventricles Sometimes called the univentricular heart, a functional single ventricle is a heart that only has one usable pumping chamber either in the native state or with surgical correction, and is one of the most challenging diseases a clinician and imager faces. The detailed anatomy is highly variable as the ventricles, morphologically, can be an RV or LV. It can also be D-looped (right-handed ventricular geometry) or L-looped (left-handed ventricular geometry). Examples of single ventricles are diseases such as HLHS (functional single RV) or double-inlet LV and tricuspid atresia (functional single LV) to name a few. In addition, surgical repair involves staged reconstruction in which the patient undergoes varying physiologic changes from a volume-loaded single ventricle to a volume-unloaded one and from the systemic and pulmonary circulations connected in parallel to both circulations

hooked up in series. The imager must understand patients in the native state along with the surgical repair to successfully contribute to the management and care. A detailed discussion of these nuances is beyond the scope of this chapter and the reader is referred to textbooks of pediatric cardiology for details; however, a short is provided synopsis is in order to understand the subsequent imaging. In the native state, surgery may not even be needed for certain lesions until 4 to 6 months of age as in tricuspid atresia, normally related great arteries, and a restrictive VSD or PS. If the patient’s oxygen saturation is acceptable and does not develop heart failure, the pulmonary blood flow is adequate but restricted and maintained by the usable LV. The systemic venous return crosses an ASD, mixes with pulmonary venous return in the LA and LV, and gets pumped to both circulations. On the other hand, patients with HLHS need immediate surgery—the Norwood Stage I procedure [25]—which involves an atrial septectomy, transection of the main pulmonary artery, and anastomosis and homograft augmentation with the hypoplastic aorta and placement of a systemic to pulmonary artery shunt or Sano (RV to pulmonary artery) conduit. The ventricle is volume loaded at this stage. At 4 to 6 months of age, the bidirectional superior cavopulmonary connection (BSCC) is performed (either a hemiFontan or bidirectional Glenn), which creates a superior vena cava to pulmonary artery anastomosis and prevents blood from the superior vena cava entering into the atrium along with ligation of the systemic to pulmonary artery connection. The ventricle is thought to be volume unloaded at this time, however, because many patients develop aorto-pulmonary collaterals, this may not be the case in many patients [26]. Because only a portion of the systemic venous return enters the lungs, cardiac output is maintained at the expense of cyanosis. Finally, at 2 years of age, Fontan procedure is performed [27], placing the systemic and pulmonary circulations in series by baffling inferior vena cava blood to the lungs via either a baffle or conduit. The systemic venous return at this stage flows passively into the lungs and the ventricle is again thought to be volume unloaded. In a number of procedures, a fenestration is purposely created between the systemic and pulmonary venous pathways to allow for blood to shunt from right to left when there is increased pulmonary vascular resistance to maintain cardiac output at the expense of cyanosis, similar in concept to the BSCC. The type of imaging and algorithms to be used are dependent upon the patient’s stage of surgery. In general, when the patient first presents for medical attention, the first exam is a CXR, followed by echocardiography with Doppler examination. The patient can usually (but not always) undergo the Norwood stage I operation with just this information alone. Postoperatively, in follow-up and at other stages of surgery, CXRs, echocardiography, and CMR are the mainstays of imaging with cardiac catheterization

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F ig u re 1 5 . 1 2 â•… Cine cardiac magnetic resonance of the 3-chamber

view in a single ventricle (mal-aligned atrioventricular canal to the right ventricle) after Fontan.

used for interventional procedures (eg, placement of coils, balloon angioplasty). However, in the pediatric age range, at least one cardiac catheterization is undertaken for pressure measurements. As the patient grows, as mentioned in the TGA section, echocardiography is less useful and CMR is relied more and more, although this varies between institutions. CT scanning is used when CMR is contraindicated. The CXR is utilized to assess the degree of pulmonary blood flow and heart size in the native state. In addition, for patients with heterotaxy syndromes, the stomach bubble, tracheobronchial anatomy, and sidedness of the liver and aortic arch may be assessed. Postoperatively, the CXR is used to assess the heart size (eg, pericardial effusion), for pleural effusions or ascites, to assess pulmonary flow by checking on pulmonary vascular markings, and to visualize device placement or endotracheal tube/catheter position. Echocardiography is the primary imaging modality utilized from in utero diagnosis through the middle of childhood (Figure 15.13). The diagnosis of single ventricle is made by determining the relative sizes of both ventricles and associated abnormalities including the sizes of the great vessels. As functional single ventricles comprise a myriad of lesions, a systematic approach must be used. Systemic and pulmonary venous connections need to be defined (eg, interrupted inferior vena cava with azygous continuation to a superior vena cava) along with the segmental connections (atria to ventricle and ventricle to great artery connections), the presence and size of the ductus arteriosus, the sidedness of the aortic arch, the extent of aortic arch obstruction, ventricular shortening, and the status of the ASD. An intact atrial septum with HLHS is an emergency and requires urgent intervention. In addition, the echocardiographer must define whether the ventricles can be separated, even if both are of good size. Color flow mapping is used extensively to determine anatomic and physiologic parameters such as detection of anomalous veins, to determine the direction and amount of flow across the ASD and

F ig u re 1 5 . 1 3 â•… Echocardiographic apical view of a patient with

hypoplastic left heart syndrome after a bidirectional cavopulmonary connection.

patent ductus arteriosus, to assess valve function, to detect aortic arch obstruction, and to aid in determining systemic and pulmonary venous connections. Echocardiography as well as CMR [28,29] play key roles in the postoperative assessment of the patient; however, at different stages of reconstruction, different structures are important to focus on. Ultrasound is usually the first examination for reasons mentioned above. However, because of ultrasound limitations as also mentioned above, CMR plays an important role in this area and has increasingly been used to supplant cardiac catheterization as well. The combination of CMR and echocardiography is a complete noninvasive package to determine if the patient can proceed directly to surgery or if cardiac catheterization is indicated. The imager’s goal is a complete assessment of anatomy, function, and physiology postoperatively. At all stages, the following is the minimum a CMR examination should include: (a) aortic arch imaging; (b) pulmonary artery imaging (Figure 15.14) [30]; (c) pulmonary or systemic venous obstruction including the status of the ASD; (d) ventricular outflow tract obstruction (Figure 15.15); (e) ventricular function (Figure 15.12); (f) velocity mapping to assess for cardiac index, Qp/Qs, relative flows to both lungs, and regurgitant fraction of the semilunar (and indirectly) atrioventricular valve; and (g) anomalous venous structures. In the native state, a detailed CMR assessment of the anatomy is needed as less is known about the patient’s anatomy than at other stages. Understanding the presence of anomalous venous structures, visceral situs, presence or absence of an inferior vena cava, and so on is essential to

2 5 0Multimodality Imaging in Cardiovascular Medicine

F ig u re 1 5 . 1 4 â•… Cine cardiac magnetic resonance of the superior vena cava to pulmonary artery anastomosis in a single ventricle after Fontan; the aortic to pulmonary anastomosis is also visualized.

F ig u re 1 5 . 1 5 â•… Cine cardiac magnetic resonance of the aortic to pul-

monary anastomosis and the ventricular outflow tract in a single-ventricle patient.

the patient’s care. In addition, assessment of ventricular function and valve insufficiency is also necessary as some patients may have been compromised at birth; see echocardiography section above. After the Stage I reconstruction, assessment of the aortic to pulmonary anastamosis, the RV to pulmonary artery conduit or aortic to pulmonary shunt (generally with dark-blood imaging or gadolinium), and the aortic arch for obstruction are demanded. Qp/Qs is obtained by velocity mapping. The status of the ASD (Figures 15.12 and 15.13) should also be assessed. In addition, since this is a volume-loaded stage, ventricular function is also a key imaging goal. After the BSCC, besides the anatomy, physiology, and function noted above, the major focus in this exam is on the superior vena cava to pulmonary artery connection— either the bidirectional Glenn or hemiFontan. This can be done with cine or gadolinium sequences. If a hemiFontan was performed, leaks into the atrium from the superior

F ig u re 1 5 . 1 6 â•… 3-dimensional reconstruction from gadolinium enhanced of a single ventricle after bilateral bidirectional Glenn connection and Fontan. The Fontan baffle, superior vena cava right pulmonary artery, and aortic to pulmonary anastomosis are clearly seen.

vena cava to pulmonary artery anastamosis should be assessed. Qp/Qs can be calculated by flow in the superior vena cava or in both branch pulmonary arteries; however, recent data suggest that velocity mapping in all pulmonary veins is much more appropriate since this takes into account aortic to pulmonary collateral flow [26], which is much different from catheterization-derived data. After Fontan completion, the most important structure to image is the systemic venous pathway for obstruction, thrombus, and fenestration flow. Evaluating ventricular performance with such parameters as end-diastolic volume, ejection fraction, and cardiac output is essential as these patients generally have ventricular dysfunction. Gadolinium-enhanced imaging (Figure 15.16) can help determine the presence of collaterals and assess the aortic arch, and velocity mapping plays a key role in measuring cardiac output, relative flows to both lungs, and assessing collateral flow.

jâ•… CON CL USIO N Today’s modern care of the patient with CHD relies heavily on multimodality imaging to deliver high-quality medicine with excellent outcomes. Advances in multimodality imaging with up-to-date hardware and software technologies have allowed health care providers to peer into the cardiovascular system with clarity never dreamed of even 10 years ago. The key to better medical and surgical treatment is to utilize the many imaging techniques in the most efficient manner. Future advances and even newer imaging technologies will certainly change the landscape for the care of the patient with CHD in the coming years.

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jâ•… REFERENCES â•‡ 1. Hoffman JIE, Kaplan S. The incidence of congenital heart disease. J Am Coll Cardiol. 2002;39:1890–1900. â•‡ 2. Fyler DC, Buckley LP, Hellenbrand WE. Report of the New England Regional Infant Cardiac Program. Pediatrics. 1980;65(2):377–461. â•‡ 3. Fogel MA, Weinberg PM, Hoydu A, et al. The nature of flow in the systemic venous pathway in Fontan patients utilizing magnetic resonance blood tagging. J Thorac Cardiovasc Surg. 1997;114:1032–1041. â•‡ 4. Beekman R, Hazekamp M, Sobotka M, et al. A new diagnostic approach to vascular rings and pulmonary slings: the role of MRI. Magn Reson Imaging. 1998;16(2):137–145. â•‡ 5. Fogel MA, Weinberg PM, Chin AJ, Fellows KE, Hoffman EA. Late ventricular geometry and performance changes of functional single ventricle throughout staged Fontan reconstruction assessed by magnetic resonance imaging. J Am Coll Cardiol. 1996;28(1):212–221. â•‡ 6. Beerbaum P, Korperich H, Barth P, et al. Non-invasive quantification of left-to-right shunt in pediatric patients. Phase-contrast cine magnetic resonance imaging compared with invasive oximetry. Circulation. 2001;103:2476–2482. â•‡ 7. Finn JP, Baskaran V, Carr JC, et al. Low-dose contrast-enhanced threedimensional MR angiography with subsecond temporal resolution—initial results. Radiology. 2002;224:896–904. â•‡ 8. Fogel MA, Weinberg PM, Hubbard A, et al. Diastolic biomechanics in normal infants utilizing MRI tissue tagging. Circulation. 2000;102:218–224. â•‡ 9. Pennell DJ, Sechtem UP, Higgins CB, et al. Clinical indications for cardiovascular magnetic resonance (CMR): Consensus Panel report. Eur Heart J. 2004;25(21):1940–1965. 10. Bluemke DA, Achenbach S, Budoff M, et al. Noninvasive coronary artery imaging magnetic resonance angiography and multidetector computed tomography angiography: a scientific statement from the American Heart Association Committee on cardiovascular imaging and intervention of the council on cardiovascular radiology and intervention, and the councils on clinical cardiology and cardiovascular disease in the young. Circulation. 2008;118:586–606. 11. National Cancer Institute. Radiation risks and pediatric computed tomography (CT): a guide for health care providers. http://www .cancer.gov/cancertopics/causes/radiation-risks-pediatric-CT. Accessed April 22, 2009. 12. Holmvang G. A magnetic resonance imaging method for evaluating atrial septal defects. J Cardiovasc Magn Reson. 1999;1:59–64. 13. Hartnell GG, Sassower M, Finn JP. Selective presaturation magnetic resonance angiography: new method for detecting intracardiac shunts. Am Heart J. 1993;126:1032–1034. 14. Beerbaum P, Korperich H, Esdorn H, et al. Atrial septal defects in pediatric patients: noninvasive sizing with cardiovascular MR imaging. Radiology. 2003;228:361–369. 15. Boxer RA, LaCorte MA, Singh S, et al. Nuclear magnetic resonance imaging in evaluation and follow-up of children treated for coarctation of the aorta. J Am Coll Cardiol. 1986;7:1095–1098.

16. Steffens JC, Bourne MW, Sakuma H, et al. Quantification of collateral blood flow in coarctation of the aorta by velocity-encoded cine magnetic resonance imaging. Circulation. 1994;90:937–943. 17. Senning A. Surgical correction of transposition of the great vessels. Surgery. 1959;45(6):966–980. 18. Mustard WT. Successful two-stage correction of transposition of the great vessels. Surgery. 1964;55:469–472. 19. Higgins CB, Byrd BF III, Farmer DW, Osaki L, Silverman NH, Cheitlin MD. Magnetic resonance imaging in patients with congenital heart disease. Circulation. 1984;70(5):851–860. 20. Sorensen TS, Korperich H, Greil GF, et al. Operator-independent isotropic three-dimensional magnetic resonance imaging for morphology in congenital heart disease: a validation study. Circulation. 2004;110(2):163–169. 21. Kersting-Sommerhoff BA, Diethelm L, Teitel DF, et al. Magnetic resonance imaging of congenital heart disease: sensitivity and specificity using receiver operating characteristic curve analysis. Am Heart J. 1989;118(1):155–161. 22. Taylor AM, Dymarkowski S, Hamaekers P, et al. MR coronary angiography and late-enhancement myocardial MR in children who underwent arterial switch surgery for transposition of great arteries. Radiology. 2005;234:542–547. 23. Pennell DJ, Sechtem UP, Higgins CB, et al. Clinical indications for cardiovascular magnetic resonance (CMR): Consensus Panel report. J Cardiovasc Magn Reson. 2004;6(4):727–765. 24. Giardini A, Lovato L, Donti A, et al. Relation between right ventricular structural alterations and markers of adverse clinical outcome in adults with systemic right ventricle and either congenital complete (after Senning operation) or congenitally corrected transposition of the great arteries. Am J Cardiol. 2006;98(9):1277–1282. 25. Norwood WI, Lang P, Hansen DD. Physiologic repair of aortic atresia-hypoplastic left heart syndrome. N Engl J Med. January 6, 1983;308(1):23–26. 26. Whitehead KK, Gillespie MJ, Harris MA, Fogel MA, Rome JJ. Noninvasive quantification of systemic to pulmonary collateral flow: a major source of inefficiency in patients with superior cavopulmonary connections. Circ Cardiovasc Imaging. 2009;2:405–411. 27. Fontan F, Baudet E. Surgical repair of tricuspid atresia. Thorax. 1971;26(3):240–248. 28. Fogel MA, Weinberg PM, Chin AJ, Fellows KE, Hoffman EA. Late ventricular geometry and performance changes of functional single ventricle throughout staged Fontan reconstruction assessed by magnetic resonance imaging. J Am Coll Cardiol. 1996;28(1):212–221. 29. Fogel MA. Cardiac magnetic resonance of single ventricles. J Cardiovasc Mag Resonan. 2006;8(4):661–670. 30. Fogel MA, Ramaciotti C, Hubbard AM, Weinberg PW. Magnetic resonance and echocardiographic imaging of pulmonary artery size throughout stages of Fontan reconstruction. Circulation. 1994;90(6):2927–2936.

16

Constrictive Pericarditis Versus Restrictive Cardiomyopathy

anDreW S. FLeTT

jâ•…PATH OPHYSIOLOGY AND PRESENTATION

j ames C. M oon

Constrictive Pericarditis Constrictive pericarditis (CP) and restrictive cardiomyopathy (RCM) are diseases with overlapping clinical presentations and diagnostic findings but very different etiology, pathological features, and treatments [1]. They are often progressive and debilitating diseases characterized by heart failure with apparently preserved systolic function, raised systemic and pulmonary venous pressures, and a low Â�cardiac output [2]. Differentiating the two is important as CP is treatable with surgical pericardial stripping but at some risk. RCM, on the other hand, can typically only be managed with medical therapy (except when RCM is a cardiac manifestation of a systemic disease) and failing these with transplantation. No single investigative gold standard test exists for differentiating RCM and CP. In clear-cut extreme cases, each imaging modality may detect all the key pathological changes and diagnosis may be straightforward. More frequently, the relative strengths of each test provide complementary information to form an overall clinical picture leading to a correct interpretation and definitive diagnosis (Table 16.1). jâ•… Table 16.1â•… Relative merits of imaging in the investigation of constrictive pericarditis and restrictive cardiomyopathy. Echo

CCT

jâ•… Table 16.2â•… Causes of constrictive pericarditis (CP) and restrictive cardiomyopathy (RCM) RCM Causes

CP Causes

CMR

Idiopathic

Familial (including sarcomeric disease)

Infection— viral/TB

Endomyocardial fibrosis (chronic hypereosinophilia)

Cardiac surgery and other interventions

Infiltrative diseases—Gaucher’s disease, Hurler’s disease, amyloidosis, and sarcoidosis

Irradiation (esp. mantle)

Storage diseases—hemochromatosis, glycogen storage disease, Anderson– Fabry disease

Uremia

Cardiac surgery

Malignancy

Irradiation

Autoimmune (SLE, rheumatoid arthritis)

Carcinoid heart disease Metastatic cancer Drug induced—Anthracycline, procainamide, hydralazine

Accessibility

111

11

1

Radiation avoidance

111

2

111

Anatomy: soft tissue

11

11

111

Anatomy: calcification

1

111

2

Systolic function

111

1

111

Diastolic function

111

2

1

Hemodynamics

11

1

11

Valves

111

1

11

Tissue characterization

1

1

111

Tethering

1

2

11

Echo, echocardiography; CCT, computed cardiac tomography; CMR, cardiovascular magnetic resonance. 2 52

CP may be caused by various underlying pathologies (see Table 16.2). In CP, the pericardium becomes thickened and noncompliant, often adherent to the myocardium and encasing the heart. This anatomical change can be visualized with imaging techniques, but the hemodynamic changes must also be discerned for the diagnosis to be made. In the normal heart, during inspiration, intrathoracic pressure falls, aiding right heart filling by increasing the pressure gradient between the extrathoracic systemic veins and right atrium [2], unlike those to the left atrium that are intrathoracic and so less influenced by intrathoracic pressure changes. In CP, the fixed total volume provided by the encasing pericardium means that filling is terminated early and abruptly, occurring almost exclusively in early diastole. It also means that filling of one ventricle occurs at the expense of the other depending on the phase of respiration—so-called ventricular interdependence. Marked elevation in atrial and ventricular filling pressures also occurs with a fixed, impaired stroke volume.

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Constrictive Pericarditis Versus Restrictive Cardiomyopathy2 5 3

CP presents with progressive nonspecific symptoms leading to reduced exercise tolerance and biventricular (but predominantly right) heart failure (edema, ascites, hepatomegaly) (see Table 16.3). Chest x-ray (CXR) may be very helpful in the diagnosis of CP especially if it is TB or posttraumatic in origin as heavy calcification of the pericardium may be seen, particularly on the lateral projection (see Figure 16.1). A normal cardiac silhouette, dilated LA and SVC may be seen in either condition. The electrocardiogram in both conditions is typically nondiscriminatory. Low voltages and nonspecific ST-T wave changes may be present, and atrial arrhythmias are common. Restrictive Cardiomyopathy Restrictive filling is the final common end point in systolic and diastolic heart failure, whatever the cause. RCM is a disease characterized by abnormal myocardium resulting in restrictive filling, elevated pressures, and reduced diastolic volume of either or both ventricles with preserved

jâ•… Table 16.3â•… Clinical signs of restrictive cardiomyopathy (RCM) and constrictive pericarditis (CP) Raised jugular venous pressure with rapid x and y descents Kussmaul’s sign (inspiratory increase in systemic venous pressure) Hepatomegaly Ascites Pedal edema Third heart sound/pericardial knock Functional tricuspid and mitral incompetent murmurs

radial systolic function and normal wall thickness [3]. The distinction between RCM and cardiomyopathies with hypertrophy and restrictive physiology is contentious, and there is overlap and some ambiguity between phenotypes depending on the classification used [4]. The prime example of this is cardiac amyloidosis, which is the exemplar for restrictive physiology and yet manifests as LVH with systolic dysfunction. In RCM, ventricular compliance to filling is reduced throughout diastole, and unlike CP in which pressures may equilibrate in all 4 chambers, left sided and pulmonary artery systolic pressures are typically higher than right-sided pressures due to the greater intrinsic stiffness of the LV, with less ventricular interdependence. Unlike CP, inspiratory effects on ventricular systolic pressures are not discordant, and there is a relative lack of respiratory variation in cardiac filling with decreased mitral and tricuspid flow velocity during atrial contraction. Patients with RCM present in an almost identical way to those with CP with signs and symptoms of biventricular heart failure. (For causes of RCM, see Table 16.2.)

jâ•… INV ESTIGATION Cardiac Catheterization Hemodynamic measures at cardiac catheterization have been used as the gold standard for the differentiation of CP from RCM [2]. Classical findings include nearly equal (and elevated) diastolic pressures in all 4 chambers of the heart in CP, reflecting the global effect of encasement, whereas in RCM, slightly higher (.5 mm/Hg) left-sided pressures are usually found. A dip-plateau, or square root-like, waveform

F ig u re 1 6 . 1 â•… The posteroanterior (left panel) film shows subtle pericardial calcification which is much more clearly seen on the lateral (right,

arrowed).

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Multimodality Imaging in Cardiovascular Medicine

jâ•… IMA GING Constrictive Pericarditis

Echocardiography

F ig u re 1 6 . 2 â•… Angiographic view of the left coronary system. Multiple

arterioles can be seen within the pericardium or pericardial space, which was found to be neovascularization of an infiltrative malignancy, in this case mesothelioma.

in the right ventricular manometry is classic for CP but may also occur in RCM. Respiratory variation in interventricular peak systolic pressures is nearly always present in CP, with right ventricular pressure greatest in inspiration and LV pressure greatest in expiration, unless the patient is dehydrated (diuresed, nil by mouth) at the time of catheterization. Cardiac catheterization may provide additional clues in the movement of the coronary arteries or LV gram or rarely vascularization of the pericardium indicating abnormal, and likely malignant, pericardial constriction (Figure 16.2).

F ig u re 1 6 . 3 â•… Ventricular interdependence in constriction. Left expiration, right inspiration demonstrated by cardiovascular magnetic resonance (upper) and echocardiography (lower). During pericardial stripping with positive pressure ventilation, this phenomenon is reversed.

Echocardiography is the initial imaging investigation of choice in the investigation of any form of heart failure including CP and RCM. It is readily available, portable, and does not involve ionizing radiation. The functional and morphological features of the heart can be visualized, and the high temporal resolution of echocardiography is a key advantage allowing the indirect measurement of hemodynamic variables. Pointers to CP include, first, a septal bounce/notch, although this is nonspecific [2]. Filling is rapid in early diastole; if filling in the RV is not synchronous, rapid changes in the pressure differential between the two sides of the ventricular septum can result, giving rise to a septal bounce. Second, ventricular interdependence during respiration may manifest in the short axis view during inspiration as a leftward shift of the septum and a D-shaped LV (Figure 16.3). This is not specific and may also be found in RV pressure overload (pulmonary stenosis or pulmonary hypertension), although typically this is present throughout the respiratory cycle. There are 5 Doppler variables to assess: 1. Transmitral and tricuspid inflow velocity; respiratory variability in early diastole (tricuspid increases .10% and mitral decreases on inspiration (Figure 16.4); 84% sensitivity and 91% specificity) [5] 2. Pulmonary vein diastolic velocity; respiratory variability (.18%) (79% sensitivity and 91% specificity) [5] 3. Diastolic flow reversal in hepatic vein in expiration 4. Early diastolic mitral annular velocity (Ea) using Tissue Doppler Echocardiography (TDE) (normal in

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CP, reduced in RCM, ,8 cm/s with 95% sensitivity and 96% specificity) (Figure 16.5) [5–7] 5. Color M-mode LV flow propagation velocity .1.00 m/s (74% sensitivity and 91% specificity)

Cardiac Computed Tomography A major advantage of computed tomography (CT) over other modalities is its anatomical accuracy, excellent thoracic imaging, and the ability to detect pericardial calcification [8] (Figure 16.6). Fat is easily differentiated from the pericardium,

F ig u re 1 6 . 4 â•… Transthoracic echocardiography pulsed Doppler mitral

inflow patterns during respiration. Inspiratory variation of more than 10% is suggestive of constriction.

but occasionally fluid and pericardial thickening may be confused. Typically, functional imaging is not acquired during CT for the pericardium, although with gating some insights could be achieved. Cardiac computed tomography (CCT) also permits coronary artery disease rule out with high diagnostic accuracy. Disadvantages include the use of intravenous iodine-based contrast and ionizing radiation.

Cardiovascular Magnetic Resonance Cardiovascular magnetic resonance (CMR) is used as an adjunct to echocardiography. CMR allows a thorough evaluation of anatomy, function, and volumes and allows for tissue characterization with the use of both intrinsic tissue properties and contrast-enhanced imaging. CMR provides excellent visualization of the pericardium and surrounding tissue. The thickness of the normal parietal pericardium is less than 2 mm, and pericardial thickening (.3 mm) in combination with signs of heart failure is suspicious for CP. Under some circumstances (up to 20% of cases), pericardial thickening may be absent with CP [9], particularly after high-dose mantle irradiation. Likewise, pericardial thickening alone does not necessitate constriction. The parietal pericardium is a fibrous structure with little water content, so it appears dark on T1-weighted imaging with bright surrounding fat. If calcified or densely fibrotic, the pericardium may become darker. Particular areas of pericardial involvement may be scrutinized, particularly around the venous inflows to the heart, which are important from a surgical point of view. Malignant infiltration of the pericardium may also occur causing constriction and can be visualized on CMR (Figures 16.10 and 16.11). Real-time cine imaging in short axis may be performed during inspiration and expiration in the same way as with echocardiography, with the added advantage of virtually no respiratory dependence of the field of view (Figure 16.3).

F ig u re 1 6 . 5 â•… Tissue Doppler echocardiography (TDE) allows direct measurement of myocardial velocities. Early diastolic mitral annular velocity (E’) recorded by TDE is a simple and reliable non-invasive index of LV relaxation that is also less load dependent than conventional Doppler. Because primary myocardial disease affects the rate of LV relaxation, which is usually not affected by constrictive pericarditis, E’ is a useful tool in differentiating RCM from CP with a cut off value of 8cm/s. Left with restrictive cardiomyopathy demonstrating E’<8cm/s (arrowed). On the right, TDI is normal in this patient with confirmed constriction, E’ >8cm/s (notice scale change).

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Multimodality Imaging in Cardiovascular Medicine

F ig u re 1 6 . 6 â•… Thoracic computed tomography (upper

panes) clearly show pericardial calcification (lower panes) 3D reconstruction demonstrating its circumferential nature.

F ig u re 1 6 . 7 â•… Left – echo and right – CMR

image of RCM demonstrating characterÂ� istic morphologic features – biatrial dilatation, poor long axis function (evident on cine) with normal systolic function. Note also the pleural effusion (arrow) which may indicate decompensation.

Tagging, a CMR technique whereby gridlines can be superimposed before image acquisition, clearly demonstrates myocardial and pericardial deformation during the cardiac cycle. This allows the distinction of pericardial tethering, either between the visceral and parietal layers or to the underlying epicardium. In the normal heart, the pericardium is seen to slide freely over the epicardium during longitudinal shortening. In constriction, this is lost and the taglines remain unbroken. Inflammatory pericarditis (IP) can sometimes exhibit features of constriction that can lead to diagnostic difficulty based on filling characteristics alone. This distinction is important as the management is very different, potentially requiring immunomodulation or steroids. CMR can be useful in distinguishing this with the use of enhancement

characteristics after gadolinium and the pericardial signal intensity on T1- and T2-weighted spin-echo. Normal pericardium has low signal on spin echo imaging; acutely inflamed pericardium has high signal. If the pericardium enhances after gadolinium, this would also suggest IP. Serial imaging may demonstrate changes in pericardial thickness over time. Restrictive Cardiomyopathy

Echocardiography Severe diastolic dysfunction and restrictive filling with elevated filling pressures and marked biatrial dilatation are seen (Figure 16.7). Systolic function is usually normal but may be impaired, and wall thickness is usually normal

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Constrictive Pericarditis Versus Restrictive Cardiomyopathy2 57

F ig u re 1 6 . 8 â•… Pulsed wave Doppler of a patient with restrictive cardiomyopathy and restrictive physiology. Notice the small ‘a’ wave (arrowed, giving E/A >>2) and rapid filling (87ms).

F ig u re 1 6 . 9 â•… CMR of endomyocardial fibrosis. (Left) SSFP image showing possible endocardial thrombus (arrowed), (middle) late enhancement

image showing widespread endocardial fibrosis with overlying thrombus. (Right) again in short axis.

but may become thickened in later disease or in specific etiologies. Atrial enlargement occurs as a consequence of chronic elevation of atrial pressure and may be exacerbated by mitral and tricuspid regurgitation. Atrial enlargement does occur in CP due to the same elevated pressure, but enlargement may be constrained by the encasing pericardium. Doppler provides further evidence of restrictive filling, the definition being based on transmitral Doppler flow measurement of E/A .2, deceleration time of E ,150 milliseconds (Figure 16.8), and IVRT ,70 milliseconds. Echocardiography has several limitations, including low signal-to-noise ratio of the pericardium, and is difficult in patients with poor windows. Transesophageal echocardiography may improve visualization of the pericardium but is relatively invasive and still has a narrow field of view, which means that a 3-dimensional assessment of the whole pericardium cannot easily be made.

Cardiovascular Magnetic Resonance Many of the familiar echocardiographic features are also seen by CMR (Figure 16.7) but not so easily the short time interval and flow phenomena. Signs of decompensation (such as systemic venous dilatation, hepatomegaly, effusions) or clues to etiology may also be seen with pleural or pericardial effusions (amyloid) or hilar Â�lymphadenopathy (sarcoid). CMR can be a useful tool in the assessment of patients with RCM, especially in the identification of Â�certain etiologies. Specific Restrictive Cardiomyopathy Etiologies

Eosinophilic Endomyocardial Disease Hypereosinophilic syndrome frequently involves the heart with development of endomyocardial fibrosis (EMF), an RCM. Diagnosis is frequently challenging, but imaging

2 5 8Multimodality Imaging in Cardiovascular Medicine

F ig u re 1 6 . 1 0 â•… Malignant infiltration of the pericardium, in this case causing constriction. Here avascular/hypovascular islands of necrosis

are seen both by cardiovascular magnetic resonance (CMR, left) and Cardiac Computed Tomography (CCT, right) within a few minutes of contrast Â� injection. Note the pleural effusion.

F ig u re 1 6 . 1 1 â•… Multimodality tissue characterization of abnormal pericardium. Irregular pericardial thickening on CMR (top, left) had been show by both echocardiography and cine CMR to be causing constriction (see figure 5). The thickening is shown by CMR to have hypovascular regions (top right) and to be metabolically active (bottom, PET scans). These appearances were suspected of representing malignancy but biopsy and histology demonstrated active Tuberculosis with cold abscesses.

offers the potential for improved characterization of this disease. Cardiac involvement is characterized by biventricular EMF and intracardiac apical thrombus, even when wall motion is preserved. This thrombus may lead to the appearance of apical amputation on imaging along with diastolic dysfunction. Fibrosis may manifest as thickening of the mitral valve leaflets (6 incompetence) or of the posterior wall. Increased endomyocardial echo density may be detected in some areas. The use of contrast allows detection of apical thrombus even in subjects with less favorable acoustic windows. In addition to these findings, CMR can identify thrombus [10] (with first pass perfusion and early enhancement) and focal fibrosis (with late enhancement) using gadolinium contrast (Figure 16.9).

Amyloidosis Cardiac amyloidosis is characterized by deposition of amyloid protein in the myocardium, causing an RCM. There are several forms of amyloidosis—acquired monoclonal immunoglobulin light chain (AL) amyloidosis (the commonest form), hereditary—transthyretin mutant related form (AATR), serum amyloid A (AA) form (in which cardiac involvement is rare) [11], and senile amyloid, which is common and may be underrecognized in the elderly heart. In early disease, imaging appearances may be subtle with only generic clues such as atrial dilatation. In more advanced disease, imaging may be more specific (Figure 16.12). Cardiac amyloid classically causes

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Constrictive Pericarditis Versus Restrictive Cardiomyopathy2 59

F ig u re 1 6 . 1 2 â•… Amyloidosis. Left, transthoracic echocardiography—although the gain settings here are arbitrary, there is an impression of a speckled appearance of the septum. Middle, cine Cardiovascular magnetic resonance (CMR) image and right, late gadolinium enhancement (LGE) image showing typical black blood pool with widespread subendocardial LGE. Far right, Congo red stain showing amyloid protein in the myocardium (polarized light not used for this image).

Intramyocardial T1 gradient at 2 minutes 1.0

Cumulative survival

0.8 P = 0.005 0.6

0.4

0.2

Subepic,-Subendoc,T1 > 23ms ≤ 23ms

0.0 0

300

600

900

1200

a nondilated ventricle with concentric, progressive, biventricular atrial, and ventricular thickening with diastolic dysfunction, restrictive physiology leading to eventual impairment of systolic function. Unlike LV thickening from hypertrophy, asymmetric septal hypertrophy and systolic anterior motion of the mitral valve are less common, and infiltration causes small complexes on the surface ECG. Doppler echocardiography may demonstrate restrictive filling as described. Strain and strain rate imaging are more sensitive than tissue Doppler, demonstrating longaxis dysfunction in early cardiac amyloidosis and often showing disproportionate impairment of longitudinal contraction despite apparently preserved fractional shortening. Pleural and/or pericardial effusions are common. In addition to these morphological and functional features, CMR with Gd-DTPA demonstrates characteristic contrast dynamics and late gadolinium appearances. The blood pool is characteristically dark, even early after gadolinium, and obtaining good blood/myocardial contrast is difficult. Nulling of the myocardium is challenging, and the

1500

F ig u re 1 6 . 1 3 â•… Kaplan Meier survival curves for patients with amyloidosis based on intramyocardial T1 gradient at 2 minutes. (Reproduced as open access material from Ref. 13.)

pattern of LGE is typically subendocardial, affecting all 4 chambers diffusely in up to 69% of cases [12]. The presence of LGE is not related to prognosis, but gadolinium kinetics are important, with postgadolinium intramyocardial T1 difference (at 2 minutes) between subepicardium and subendocardium predicting mortality with 85% accuracy (the greater the difference, the worse the prognosis; Figure 16.13) [13].

Sarcoidosis Sarcoidosis is a multisystem, granulomatous disease with prognosis primarily dictated by lung and cardiac involvement. At autopsy, 50% have cardiac involvement although this is not often recognized in life, presenting a significant diagnostic challenge. The spectrum and significance of echo abnormalities in cardiac sarcoid are not fully defined. Septal thinning, LV RWMAs, effusions, aneurysms, LVH, diastolic dysfunction, and valvular abnormalities can be seen in

2 6 0Multimodality Imaging in Cardiovascular Medicine

F ig u re 1 6 . 1 4 â•… Four different patients with cardiac sarcoidosis showing different manifestations. Top left, both superior and inferior papillary muscle late gadolinium enhancement (LGE); top right, transmural LGE of the anteroseptum; bottom left, isolated RV LGE; bottom right, extensive LV LGE.

advanced disease but are neither common (14%) nor specific. TEE may be more sensitive although this is anecdotal [14]. Tissue characterization techniques using tissue Doppler [15] and ultrasound integrated backscatter measuring the acoustic properties of the myocardium in the basal septum are potentially more sensitive for early cardiac involvement [16]. As well as these changes, CMR can demonstrate granulomas as high signal areas, indicating inflammation and edema with T2 weighted imaging. The sensitivity and specificity of CMR for the diagnosis of Â�sarcoidosis are high (100% and 78%) [17]. Clues to the etiology may be seen with parenchymal lung changes and/ or hilar lymphadenopathy. Contrast imaging can be helpful, producing punched out LGE in noncoronary distributions. LGE patterns can be highly variable with isolated fibrosis (LGE) of the mitral valve papillary muscles or RV infarction (Figure 16.14). CMR can also be useful in the evaluation of response to steroid treatment with resolution of areas of LGE on follow-up scans. Positron emission tomography (PET) and scintigraphy are also useful in sarcoid. 18F-fluorodeoxyglucose (FDG) is a glucose analogue and uses the same unidirectional transmembrane carrier as glucose. Its uptake is closely related to cell glucose metabolism, and it accumulates in inflammatory cells and in the myocardium and lungs of patients with sarcoidosis. It can be detected with PET with higher sensitivity than thallium-201 SPECT and Â�gallium-67 scintigraphy (albeit with low specificity) [18,19]. Thallium-201 myocardial scintigraphy may show areas of decreased uptake, and a reverse distribution (focal defects disappear during stress due to focal reversible microvascular

constriction in granuloma arterioles) is more specific. Gallium-67 scintigraphy accumulates selectively in active inflammation (therefore, it is only positive in active disease and can predict a good response to steroids) (Table 16.4). jâ•… Table 16.4â•… Guidelines for diagnosing cardiac sarcoidosis (from the Japanese Ministry of Health and Welfare) Histologic Diagnosis Group Cardiac sarcoidosis is confirmed when histologic analysis of operative or endomyocardial biopsy specimens demonstrates epithelioid granuloma without caseating granuloma Clinical Diagnosis Group In patients with a histologic diagnosis of extracardiac sarcoidosis, cardiac sarcoidosis is suspected when item (a) and one or more of items (b) though (e) are present (a)â•‡Complete right bundle branch block, left axis deviation, atrioventricular block, VT, premature ventricular contraction ($â•›Lown 2), or abnormal Q or ST-T change on the ECG or ambulatory ECG (b)â•‡Abnormal wall motion, regional wall thinning, or dilatation of the left ventricle (c)â•‡Perfusion defect by thallium-201 myocardial scintigraphy or abnormal accumulation by gallium-67 or technetium-99m myocardial scintigraphy (d)â•‡Abnormal intracardiac pressure, low cardiac output, or abnormal wall motion or depressed ejection fraction of the left ventricle (e)â•‡Interstitial fibrosis or cellular infiltration over moderate grade even if the findings are nonspecific VT, ventricular tachycardia.

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F ig u re 1 6 . 1 5 â•… Anderson Fabry disease, left; histopathological specimen stained with picrosirius red matching the late gadolinium enhancement pattern seen on the right.

Storage Diseases

jâ•… REFERENCES

Several storage diseases manifest as a RCM, in particular Anderson–Fabry disease (AFD), glycogen storage diseases (various subtypes), AMP kinase, and Danon disease (X-linked dominant). AFD is an X-linked lysosomal storage disorder caused by mutations in the gene encoding for -galactosidase A. Reduced enzyme activity results in the multiorgan intracellular accumulation of sphingolipid. In the heart, this leads to hypertrophy (left and right), often concentric, valvular dysfunction arrhythmias, heart failure, and potentially sudden death. RCM occurs late in the disease. Echocardiography detects these changes, and some more specific signs have been proposed, for example a binary appearance of LV endocardial border [20], thought to suggest endomyocardial glycosphingolipid compartmentalization, but this is disputed [21]. CMR may demonstrate a characteristic LGE pattern, primarily affecting the basal to mid inferolateral or lateral wall in the mid wall to epicardium [22]. This has been confirmed to represent fibrosis histologically, but its predilection to the inferolateral wall is not well understood (Figure 16.15). In advanced disease, extensive LGE may be present with systolic dysfunction. The other storage diseases are to date less extensively studied, but the principal pathological processes are likely to be broadly similar, particularly in late disease in which extensive fibrosis and myocyte loss play a key role.

â•‡ 1. Goldstein JA. Cardiac tamponade, constrictive pericarditis, and restrictive cardiomyopathy. Curr Probl Cardiol. 2004;29(9):503–567. â•‡ 2. Hancock EW. Cardiomyopathy: Differential diagnosis of restrictive cardiomyopathy and constrictive pericarditis. Heart. 2001;86(3):343–349. â•‡ 3. Elliott P, Andersson B, Arbustini E, et al. Classification of the cardiomyopathies: a position statement from the European Society Of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J. 2008;29(2):270–276. â•‡ 4. Maron BJ, Towbin JA, Thiene G, et al. Contemporary definitions and classification of the cardiomyopathies: an American Heart Association Scientific Statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; and Council on Epidemiology and Prevention. Circulation. 2006;113(14):1807–1816. â•‡ 5. Rajagopalan N, Garcia MJ, Rodriguez L, M et al. Comparison of new Doppler echocardiographic methods to differentiate constrictive pericardial heart disease and restrictive cardiomyopathy. Am J Cardiol. 2001;87(1):86–94. â•‡ 6. Garcia MJ, Rodriguez L, Ares M, Griffin BP, Thomas JD, Klein AL. Differentiation of constrictive pericarditis from restrictive cardiomyopathy: assessment of left ventricular diastolic velocities in longitudinal axis by Doppler tissue imaging. J Am Coll Cardiol. 1996;27(1):108–114. â•‡ 7. Ha J-W, Ommen SR, Tajik AJ, et al. Differentiation of constrictive pericarditis from restrictive cardiomyopathy using mitral annular velocity by Tissue Doppler Echocardiography. Am J Cardiol. 2004;94:316–319. â•‡ 8. Axel L. Assessment of pericardial disease by magnetic resonance and computed tomography. J Magn Reson Imaging. 2004;19(6):816–826. â•‡ 9. Talreja DR, Edwards WD, Danielson GK, et al. Constrictive pericarditis in 26 patients with histologically normal pericardial thickness. Circulation. 2003;108(15):1852–1857. 10. Srichai MB, Junor C, Rodriguez LL, et al. Clinical, imaging, and pathological characteristics of left ventricular thrombus: a comparison of contrast-enhanced magnetic resonance imaging, transthoracic echocardiography, and transesophageal echocardiography with surgical or pathological validation. Am Heart J. 2006;152(1):75–84. 11. Falk RH. Diagnosis and management of the cardiac amyloidoses. Circulation. 2005;112:2047–2060. 12. Maceira AM, Joshi J, Prasad SK, et al. Cardiovascular magnetic resonance in cardiac amyloidosis. Circulation. 2005;111(2):186–193. 13. Maceira A, Prasad S, Hawkins P, Roughton M, Pennell D. Cardiovascular magnetic resonance and prognosis in cardiac amyloidosis. J Cardiovasc Magn Reson. 2008;10(1):54.

jâ•… CONCL USIO N CP and RCM have very different etiologies but present with similar clinical pictures. In addition to core clinical skills (history, examination, simple investigations), using multimodality imaging is the best approach to their differentiation. Interpretation of imaging must be soundly based within the clinical context and weighted on the relative strengths of each modality.

2 62

14. Hourigan LA, Burstow DJ, Pohlner P, Clarke BE, Donnelly JE. Transesophageal echocardiographic abnormalities in a case of cardiac sarcoidosis. J Am Soc Echocardiogr. 2001;14(5):399–402. 15. Smedema JP. Tissue Doppler imaging in cardiac sarcoidosis. Eur J Echocardiogr. 2008;9(4):579–580. 16. Hyodo E, Hozumi T, Takemoto Y, et al. Early detection of cardiac involvement in patients with sarcoidosis by a non-invasive method with ultrasonic tissue characterisation. Heart. 2004;90(11):1275–1280. 17. Smedema JP, Snoep G, van Kroonenburgh MP, et al. Evaluation of the accuracy of gadolinium-enhanced cardiovascular magnetic resonance in the diagnosis of cardiac sarcoidosis. J Am Coll Cardiol. 2005;45(10):1683–1690. 18. Doughan AR, Williams BR. Cardiac sarcoidosis. Heart. 2006; 92(2):282–288.

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19. Smedema JP, van Kroonenburgh MJPG, Snoep G, Bekkers SCAM, Gorgels AP. Diagnostic Value of PET in Cardiac Sarcoidosis. J Nucl Med. 2004;45(11):1975. 20. Pieroni M, Chimenti C, De Cobelli F, et al. Fabry’s disease cardiomyopathy: echocardiographic detection of endomyocardial glycosphingolipid compartmentalization. J Am Coll Cardiol. 2006;47(8):1663–1671. 21. Kounas S, Demetrescu C, Pantazis AA, et al. The binary endocardial appearance is a poor discriminator of Anderson-Fabry disease from familial hypertrophic cardiomyopathy. J Am Coll Cardiol. 2008;51(21):2058–2061. 22. Moon JCC, Sachdev B, Elkington AG, et al. Gadolinium enhanced cardiovascular magnetic resonance in Anderson–Fabry disease: evidence for a disease specific abnormality of the myocardial interstitium. Eur Heart J. 2003;24(23):2151–2155.

17 I

Differential Diagnosis of Cardiomyopathies

CH irine ParSai

jâ•…T ECHNIQUE

Ro rY O’ HanL on

Echocardiography

Sanj aY K. PraSaD

Transthoracic echocardiography (TTE) is generally the first step in the diagnosis of a cardiomyopathy and is a readily available and inexpensive bedside tool. 2-dimensional (2D) grey-scale images of long-axis, short-axis, and apical views of the heart are obtained systematically to measure left (LV) and right ventricular (RV) dimensions (using M-mode) and systolic function (Figure 17.1) [2,3]. Doppler data provide extensive information on the presence and degree of diastolic function, valve disease, shunt detection, and assessment of intracardiac pressures (eg, hemodynamic impact of a pericardial effusion) [4–7]. The safety of the procedure allows repeated follow-up even during pregnancy. However, the diagnostic yield of the technique relies on the experience of the echocardiographer and adequate acoustic window, which are mainly dependant on patient’s body habitus [8,9]. Additionally, although biventricular systolic and diastolic assessment can be readily assessed, tissue characterization of the abnormal myocardium on standard 2D echocardiography is challenging especially in the early stages of the disease [10]. Recently, tissue Doppler imaging (TDI) has been extensively validated as a way to quantify myocardial motion (velocity), deformation (strain), and contractility (strain rate) in a variety of cardiac pathologies in 2D (radial and longitudinal directions) (Figure 17.2) [11,12].Thus, a highintensity myocardial signal with a high temporal resolution can be detected. This provides a number of opportunities with a better assessment of global LV systolic and diastolic function, regional function (distinction between infarcted and noninfarcted segments, regional abnormal myocardium as seen in early stages of dilated cardiomyopathies), and interrogation of mechanical activity (eg, searching for mechanical dyssynchrony in LBBB). The recent advent of speckle tracking provides similar information in a semiautomated fashion, directly from a grey-scale image and in 3-dimensions (3D) (radial, circumferential, and longitudinal motion). It is less angle dependant than TDI [13]. Further validation of the technique is ongoing. Contrast echocardiography has been introduced in clinical practice to assess myocardial perfusion following

Cardiomyopathies represent a heterogeneous group of chronic, progressive diseases of the myocardium unrelated to coronary artery disease, hypertension, valvular disease, or congenital heart disease and exhibiting a distinct pattern of morphological, functional, and electrophysiological changes. They are either confined to the heart or are part of generalized systemic disorders often leading to cardiovascular death or progressive heart failure [1]. Identifying the specific etiology of a cardiomyopathy can prove challenging but is essential to guide patients’ treatment, to perform preventive screening of relatives, and to determine patient’s short-term and long-term prognosis. Suggestive symptoms, an abnormal physical examination, and/or ECG often lead in the initial evaluation to selected laboratory testing, conventional imaging investigations (echocardiography, radionucleotide imaging), and invasive testing (coronary angiography). However, the large overlap of Â�features between cardiomyopathies, particularly in the early stages, the various phenotypic expressions of the same disease, and the lack of symptoms in 30% of patients contribute to the challenge of establishing the diagnosis. New echocardiographic techniques (tissue Doppler imaging, speckle tracking, stress echocardiography), cardiovascular magnetic resonance imaging (CMR), and technical advances in computed tomography (CT) provide powerful tools to face this challenge. The variety and complementary nature of noninvasive tests can therefore offer an alternative to invasive testing in these patients, and by combining different imaging modalities, a more accurate diagnosis can be made with important prognostic implications. A brief overview of technical characteristics of each modality will be discussed followed by their use to detect the most frequent cardiomyopathies.

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F i g u r e 1 7 . 1 â•… Standard transthoracic echo acquisition in dilated cardio-

myopathy. Parasternal long-axis (A) and short-axis views (B) are obtained from which M-mode measurements providing dimensions and wall thickness are measured. (C–E) Apical long-axis views of the heart (4-chamber, 2-chamber, and 3-chamber views) assessing long-axis systolic function, cavity size, and presence of valve disease. Standard Doppler acquisition of the transmitral flow to assess left ventricular (LV) diastolic filling (F) and LV outflow velocity (G) to measure stroke volume is performed.

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F i g u r e 1 7 . 2 â•… Examples of normal longitudinal tissue Doppler-derived traces. Motion (displayed by velocity traces, (A) arrow pointing to peak systolic velocity), longitudinal deformation (B, arrow pointing to peak systolic strain), and contractility (C, arrow pointing to peak systolic strain rate) at specific points within the myocardium can be measured.

the injection of nonionizing contrast agents capable of crossing pulmonary vascular bed and hence achieving left heart opacification. These also help in the identification of LV apical thrombus and provide a way to improve endocardial delineation in patients with suboptimal acoustic window (Figure 17.3). Myocardial contractile reserve and coronary reserve can be assessed during the infusion of increasing doses of dobutamine following a stress echo protocol. Similar data can be obtained during graded exercise echocardiography.

Cardiac Magnetic Resonance CMR has emerged as a useful tool in clinical practice allowing image acquisition in any selected planes regardless of body habitus, in a 30- to 45-minute time frame, free of ionizing radiation, and using relatively safe gadolinium-based contrast agents. In a single examination, a morphological 3D analysis of cardiac anatomy and function, perfusion, valvular flow, coronary and peripheral angiography, as well as detection and characterization of pathological myocardium through a wide range of specific noncontrast

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F i g u r e 1 7 . 3 â•… Contrast echocardiography can be used to better delineate left ventricular (LV) apex. (A) suspicion of apical thrombus, confirmed

after injection of contrast (B). The thrombus is not opacified by the LV contrast (arrow).

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and contrast-enhanced images can be obtained. Following an initial gross assessment of cardiac anatomy, important shunts, anomalous pulmonary venous drainage, or congenital anomalies using transaxial, coronal, and sagittal HASTE (Half-Fourier acquisition Â�single-shot turbo spinecho) imaging, dynamic images of the heart are acquired along its long axis and short axis using gradient-echo steady-state free precession (eg, TrueFISP) cine imaging (Figure 17.4). CMR is validated as the gold standard imaging tool to quantify biventricular volumes and function using short-axis cine images of the LV and RV acquired from the base to the apex (Figure 17.5). The availability of normalized values for CMR measured dimensions, corrected for age, sex, and body surface area, helps to establish subtle ventricular abnormalities and provides a more

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F i g u r e 1 7 . 4 â•… Standard acquisition of the initial views of the left ventricular (LV) and right ventricular (RV) in a patient with a dilated cardiomyopathy (A) 2-chamber, (B) 4-chamber, (C) LV outflow tract, (D) LV outflow tract with a cut through the aortic root, (E) RV outflow tract, (F) short axis).

suitable method for follow-up of serial measurements given the superior interstudy reproducibility over other imaging modalities [14–18]. Tissue characterization can also be performed by the use of both intrinsic and extrinsic contrast imaging sequences. The T2-weighted sequence, short tau inversion recovery (STIR), is weighted toward increasing signal intensity from water and nulls signal from fat. It is used to identify areas of increased myocardial water content, indicative of myocardial edema and inflammation. Myocardial T2*-weighted imaging exploits the loss of signal owing to greater field inhomogeneities. It is used to assess myocardial iron since iron is ferromagnetic and leads to a dosedependent breakdown in field homogeneity, which can be quantified [19]. Valvular heart disease is assessed using

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F i g u r e 1 7 . 5 â•… Biventricular volumes can be obtained by manual tracing of endocardial borders in systole (A) and diastole (B) of all short-axis

slices from base to apex of the left ventricular.

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F i g u r e 1 7 . 6 â•…Example of gridline tagging in a patient with pulmonary hypertension and right ventricular hypertrophy. Distortion of myocardial markers over time (A) end diastole, (B) systole, provides information on myocardial strain (deformation).

velocity flow mapping. Although the temporal resolution is inferior to echocardiography, reproducible results can be obtained. Several studies have shown good agreement between the 2 imaging tools in valvular assessment [20,21]. Similar to echocardiography’s tissue Doppler velocity imaging, myocardial tagging can quantify cardiac deformation and assess contraction and relaxation in the radial, longitudinal, and circumferential directions [22] (Figure 17.6). Perfusion can be assessed at the myocardial level. Following administration of intravenous gadolinium contrast into a peripheral vein (0.1–0.2 mmol/kg body weight), the passage of the contrast through the right heart, the left heart, and the myocardium can be followed, providing information about regional myocardial perfusion at rest and perfusion reserve during administration of adenosine. Imaging performed immediately (1–3 minutes) following intravenous gadolinium contrast agent is a sensitive tool to detect intracardiac thrombi by providing the best delineation between the enhanced blood pool and myocardium on one side and the avascular dark thrombus on the other side. Late gadolinium enhancement (LGE)

imaging is then performed approximately 5 to 20 minutes after gadolinium administration. Due to its volume of distribution and washout kinetics, it accumulates in areas of increased extracellular space. The presence of LGE is indicative of abnormal myocardial interstitium such as myocardial fibrosis and infarction, and the pattern of enhancement can significantly improve the ability to establish a concrete diagnosis and also provides important prognostic information [23,24]. Cardiac Computed Tomography The improvement in CT technology has made it an attractive tool for cardiac and cardiovascular imaging. Two types of scanners, electron beam computed tomography (EBCT) and multidetector row or multislice CT scanners (MDCT or MSCT), are routinely used to image the beating heart, offering a temporal resolution below 100 milliseconds. The availability of dual source MDCT scanners reduces the temporal resolution further to 83 milliseconds, thereby facilitating imaging without the need for beta blockers [25].

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F i g u r e 1 7 . 7 â•… Coronary contrast computed tomography angiography (A) disÂ� playing a patent right coronary artery arising from the right coronary cusp. The 3-dimensional reconstruction confirms presence of unobstructed coronary arteries (B).

Cardiac computed tomography (CCT) is an interesting resource providing a fast and accurate 3D assessment of the coronaries and myocardium in a 15- to 25-second time frame, even in patients with pacing devices. However, CCT requires exposure to ionizing radiation and iodinated contrast, limiting its use in renal failure, pregnancy, and for serial follow-up over time. Following reconstructions of short-axis, long-axis, and transaxial images, CCT has been demonstrated to be accurate for the measurement of LV and RV mass, volumes and ejection fraction, and quantification of calcification on mitral and aortic valves. However, specifically sequenced CMR and echocardiography appear superior for assessing valve function and volumes [26–31]. Quantification of coronary artery calcification with noncontrast CCT has been established as a mean to provide individualized cardiovascular risk assessment and estimation of atherosclerotic plaque burden [32,33] (Figure 17.7). Contrast coronary CT angiography (CTA) performed after injection of iodinated contrast during a prolonged breath hold can image the coronary artery tree. Following postprocessing reconstructions, major epicardial segments can be analyzed with a high sensitivity and specificity for the diagnosis of significant obstructive coronary artery disease [34]. Its high negative predictive value provides a useful way of excluding coronary artery disease in a dilated cardiomyopathy and an alternative to an invasive assessment. As with CMR, late cardiac enhancement with CCT is possible to help tissue characterization, but it remains inferior to CMR and is currently considered only for patients with contraindications to CMR. Although multislice CT has an increasing role in noninvasive coronary imaging, its role in detection and workup of a cardiomyopathy has been less investigated. Nuclear/CT Hybrid Devices Hybrid devices are rapidly evolving to incorporate highspeed MDCT along with positron emission tomography

(PET) and single-photon emission tomography (SPECT) detector systems. This dual modality imaging presents an opportunity to use a single piece of equipment for a combined assessment of coronary anatomy, perfusion, function, and metabolism or coronary calcification. Radiation exposure remains an issue. The use of imaging modalities in the diagnosis of cardiomyopathies is detailed for each category of cardiomyopathy, with a particular emphasis on the use of echo and CMR, most widely used in routine clinical practice.

jâ•…D IA GNOS IS OF INDIVIDUAL CARDIO MYOPATHIES Primary Cardiomyopathies

Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia ARVC/D is an underrecognized (prevalence of 1:5000) [35] genetic disorder of the desmosome, inherited as an autosomal dominant or recessive (Naxos syndrome) trait and affecting predominantly the RV. Damage to this anchoring protein complex leads to progressive myocyte detachment and death, followed by fibrofatty tissue replacement, the hallmark pathologic feature of the disease. Associated LV involvement is reported in up to 75% of patients [36]. Sudden cardiac death from arrhythmias is often the first manifestation of the disease in young adults, emphasizing the im portance of evaluating asymptomatic relatives for the disease. Presenting symptoms range from palpitations to dizzy spells or syncope, and the clinical diagnosis is challenging owing to the nonspecific nature of associated findings and the absence of a single available confirmatory diagnostic test. Taskforce ARVC guidelines aim to address these difficulties by a multiparametric approach considering structural, histologic, electrocardiographic, arrhythmic, and familial features into major and minor criteria

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1 7 . 8 â•… Markedly dilated right ventricular (RV) seen on Transthoracic echocardiography (A) with small aneurysms identified after contrast injection. On cardiovascular magnetic resonance CMR, apical aneurysms are seen on transaxial RV views in systole (panels B and C, arrow heads) associated with mid-wall and subepicardial fibrosis in inferolateral wall and septum (D–E, arrows). Figure

according to their specificity [37]. However, despite their high specificity, these guidelines lack sensitivity, and early stages of the disease remain challenging to detect. Numerous diagnostic modalities assist in the diagnosis of ARVC and risk stratification. TTE is the initial imaging modality performed, with particular attention given to RV function, segmental dilatation, and wall motion abnormalities in the triangle of dysplasia (RV inflow, apical part, and outflow). Secondary causes of RV dilatation, such as severe tricuspid regurgitation, severe pulmonary hypertension, or shunts, can be easily detected. TTE findings suggestive of ARVC include various degrees of RV dilatation and dysfunction, enlargement of the right atrium, isolated dilatation of the RV outflow tract, increased reflectivity of the moderator band, localized aneurysm formation, and akinesia or dyskinesia of the inferior wall or apex of the RV (Figure 17.8). However, owing to the complex shape of the RV, imaging such subtle abnormalities with confidence can be very challenging with TTE. In addition, incomplete visualization of the entire free wall can limit wall-motion abnormality detection. Contrast echo may provide better visualization of the RV and improve detection of subtle areas of dyskinesia, especially in adults with difficult to acquire images. Analysis of regional RV

contractility and deformation with TDI may also help identify early changes in RV function [38,39]. However, these parameters need further evaluation in a larger population of ARVC patients. Currently, the preferred diagnostic imaging method for the RV and specifically to detect subtle RV changes outlined above is CMR. By providing a clear delineation of the RV free wall and apex, CMR allows for the detection of localized and diffuse wall motion abnormalities, such as RV dilatation, wall thinning, and aneurysmal dilatation (Figure 17.8). However, to avoid over-reading of subtle RV regional wall motion abnormality and significant interobserver variability, a high level of experience is required as well as a standardized protocol of acquisition [40]. A series of high-resolution short-axis and transaxial cines of the RV improve significantly the assessment of wall motion abnormality with a sensitivity of up to 96% and a specificity of 78% [40]. Dedicated T1-weighted spin echo images have been used to image fat in the RV. However, fat infiltration is seldom the only CMR abnormality and has proven less sensitive for ARVC diagnosis than regional RV dysfunction, even among genotyped probands of ARVC patients [41]. The disappointingly low sensitivity of this approach is linked to the fact that pathologic adipose infiltration is difficult to distinguish from normal epicardial fat surrounding the thin walled RV, and it may not be possible to detect fat infiltration in vivo until a significant proportion of the RV has been replaced by fibroadipose tissue [42]. The presence of LGE showed a high degree of correlation with endomyocardial biopsy and predicted induction of ventricular tachycardia during electrophysiologic testing [43]. Due to the high prevalence of LV involvement in ARVC, LGE is useful in identifying associated LV fibrosis [40]. Fibrosis can be seen most commonly in the mid-wall or subepicardial area of the inferolateral wall (85%) [44] (Figure 17.8). In patients with structurally severe disease, all imaging modalities are likely to provide satisfactory evaluation. In contrast, patients with milder phenotypes pose a significant diagnostic challenge and can be missed. Therefore, it is generally advised that the CMR evaluation of ARVC should be performed in dedicated, experienced CMR centers, and findings should be interpreted by experienced individuals integrating the clinical background. EBCT has been suggested as a means to better delineate segmental RV abnormalities and detect fatty infiltration by the powerful ability to characterize tissue [45]. However, ionizing radiation currently prevents its widespread use for repeated screening of relatives and follow-ups.

Hypertrophic Cardiomyopathy Hypertrophic cardiomyopathy (HCM) is a common cardiac genetic disease (0.2% of the adult general population) caused by a variety of mutations in genes typically encoding

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sarcomeric proteins and characterized by a broad and variable clinical spectrum. These mutations result in a typical histological pattern of hypertrophied myocytes arranged in a chaotic alignment scattered with patchy or transmural replacement scarring. Inherited as a dominant trait, HCM is recognized as the most common cardiac cause of sudden and unexpected death in the young (including the competitive athlete) and an important substrate for heart failure disability at any age [46,47]. It may be initially suspected because of a murmur, a positive family history, new symptoms, or an abnormal ECG pattern (75%–95% of HCM patients). Clinical diagnosis is generally established by 2D echocardiographic identification of an asymmetrically hypertrophied (wall thickness more than 13.5 mm), nondilated LV in the absence of other

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systemic or cardiac diseases that are capable of producing the magnitude of wall thickening evident (ie, systemic hypertension, aortic valve stenosis) (Figure 17.9). However, the structural changes are markedly heterogenous and indeed can be quite variable even in families with the same genetic defect. No single pattern of LV hypertrophy regarded as typical and virtually all degrees of LV wall thickness, even within normal limits, are compatible with the presence of a mutant HCM gene. Therefore, in trained athletes, modest segmental wall thickening can raise the difficult differential diagnosis between extreme physiologic LV hypertrophy and mild morphologic expression of HCM. Similar issues arise in patients with long-standing hypertension. Another challenge in practice is to distinguish LV hypertrophy mimicking HCM as a consequence of other disease states unrelated

F i g u r e 1 7 . 9 â•… Typical echocardiographic findings in Hypertrophic cardiomyopathy: asymmetrical septal hypertrophy seen in parasternal long-axis (A) and 4-chamber apical views (B). The thickened septum is responsible for an outflow tract obstruction in systole and a systolic anterior motion of the mitral valve (C: 3-chamber view in diastole, D: 3-chamber view in systole), the small arrow is pointing at the position of the anterior mitral valve leaflet, which is attracted toward the septum in systole) responsible for mitral regurgitation (E: arrow head, color flow turbulences signing mitral regurgitation). Cavity obstruction appears as a shark-tooth Doppler curve (F: small arrow) and can be quantified. Mitral regurgitation can also be noticed on the same recording (F: large arrow).

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to HCM-causing sarcomeric protein mutations, such as glycogen storage disease (Fabry’s disease) and infiltrative (amyloidosis) and inflammatory cardiomyopathies (sarcoidosis). An accurate diagnosis is of major importance as it will guide treatment, impact on familial screening, define prognosis, and help risk stratification. This can usually be resolved by noninvasive testing modalities. In typical cases, TTE will suggest the diagnosis. The addition of contrast can help visualize localized areas of hypertrophy such as apical HCM. In patients harboring a genetic defect without manifesting the phenotype, tissue Doppler echocardiography provides clues to impending LV hypertrophy by detecting diastolic dysfunction preceding the appearance of hypertrophy. By studying the various patterns of segmental deformation and contraction, TDI can help in the differential diagnosis of a hypertrophied heart. CM-related hypertrophied LV segments display areas of reduced myocardial deformation or lack of deformation due to marked myocyte disarray. Hypertensive-related LV hypertrophy is characterized on the other hand by preserved absolute myocardial deformation with a particular pattern of delayed deformation occurring in early diastole (postsystolic thickening) in LV segments submitted to the highest wall stress [48]. In confirmed HCM patients, LV outflow tract gradients can

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C 1 7 . 1 0 â•… Typical pattern of enhancement seen in various forms of Hypertrophic cardiomyopathy (HCM). Apical HCM (A: unevenly thickened apical segments) with patchy fibrosis in hypertrophied regions (arrow). (B) Marked asymmetrical septal hypertrophy with patchy dense fibrosis in the area of hypertrophy. (C) HCM with normal left ventricular wall thickness but areas of typical patchy Late gadolinium enhancement (arrow).

Figure

be easily quantified at rest and during exercise, contributing to risk stratification (Figure 17.9). Significant mitral regurgitation as a consequence of systolic anterior motion of the mitral valve can also be reliably quantified. CMR provides unique complementary information for the diagnosis of HCM. The acquisition of high spatial resolution images with excellent tissue contrast and border definition in any given planes allows accurate assessment of wall thickness in any LV segments. Segmental LV hypertrophy as seen in the apical variant of HCM, often difficult to diagnose with transthoracic echo due to signal dropout, can be easily identified [49,50]. As with echocardiography, the presence and quantification of LV outflow tract obstruction at rest or during pharmacologic stress can be performed with in-plane and through-plane velocity flow mapping, providing comparable values to those achieved by the use of echocardiographic Doppler, albeit underestimated. However, a unique feature of CMR is its ability to characterize myocardial tissue and identify areas of increased myocardial collagen and scarring in the HCM-related hypertrophied areas of the myocardium (Figure 17.10). Typical patterns of LGE are seen in HCM and are generally confined to the hypertrophied areas, distinct to those seen in DCM or ischemic heart disease. Thus, diffuse trans-septal or RV septal fibrosis, confluent

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pattern affecting the interventricular septum, or multifocal LGE can be seen (Figure 17.10). Detection of scarring by LGE has also been suggested as a way to identify patients predisposed to life-threatening electrical instability [51–54]. Architectural alterations of the microvasculature (abnormal intramural coronary arteries) as well as the mismatch between myocardial mass and coronary circulation are likely responsible for impaired coronary vasodilator reserve and episodes of myocardial ischemia, leading to myocyte death and patchy or transmural replacement fibrosis. Typical pattern of myocardial perfusion defects detected by CMR suggest associated microvascular dysfunction (Figure 17.11). Thus, the presence of LGE and microvascular ischemia detected by CMR [55] coupled to parameters of diastolic dysfunction and hemodynamic changes during exercise echo provide additional data for risk stratification and prognosis. This supports data from PET and coronary flow reserve measurements, although not currently used in routine clinical practice [56,57]. Interestingly, although reports suggest that cardiac CT can also detect fibrosis in HCM, it represents a promising and unique noninvasive tool to guide septal alcohol ablation by identifying the optimal coronary branch to target [58] (Figure 17.12).

development, giving rise to a typical spongy morphological appearance. Left ventricular noncompaction (LVNC) is often familial with predominantly autosomal dominance inheritance and may be an isolated finding (often in adult patients) or associated with other congenital heart anomalies such as complex cyanotic congenital heart disease. Presenting symptoms can be those of progressive LV systolic dysfunction and may be associated with an increased incidence of thromboembolism and ventricular arrhythmias. Noncompaction involves predominantly the apex and the lateral wall of the LV with deep intertrabecular recesses in communication with the ventricular cavity. There are a variety of morphological findings of noncompaction, including anastomosing broad trabeculae, coarse trabeculae resembling multiple papillary muscles, and interlacing smaller muscle bundles resembling a sponge. Occasionally, the entity can be somewhat subtle viewed on gross features only, although the absence of wellformed papillary muscles is a clue to the diagnosis, even when the recesses are microscopic [59]. RV involvement with large noncompacted zones has been described in up to 50% of cases. Histologically, marked areas of subendocardial fibrosis consistent with ischemic infarcts thought to be related to abnormal coronary flow reserve in noncompacted myocardium have also been noted [60].

Left Ventricular Noncompaction

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Prominent trabeculations are a normal feature of the developing myocardium in utero, and noncompaction of ventricular myocardium is thought to result from a lack of trabecular regression that occurs during normal embryonic

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F i g u r e 1 7 . 1 1 â•…Associated microvascular dysfunction in an hyper-

trophic cardiomyopathy patient is seen in areas of marked hypertrophy during adenosine stress perfusion as a typical circumferential perfusion defect (A, arrows) absent during rest perfusion (B).

F i g u r e 1 7 . 1 2 â•… Contrast computed tomography performed before alcohol ablation in an hypertrophic cardiomyopathy patient. Panel A shows the left anterior descending artery (LAD) and the first septal branches (arrows), which can be followed to define the optimal branch (B and C, arrows) vascularizing the area of hypertrophy. Courtesy of Dr L. Christiaens, Cardiologist, CHU Poitiers, France.

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Although the diagnosis of LVNC is usually made on TTE, and increasingly CMR, there is no universally accepted definition of LVNC at present. Proposed TTE criteria include measurement of trabecular recesses from a 4-chamber view in end diastole (ratio of compacted myocardium to total wall thickness #0.5) or a combination of 3 criteria: absence of coexisting cardiac abnormalities; markedly thickened LV wall consisting of 2 layers, a thin compacted epicardial layer and a heavily trabeculated endocardial layer with a ratio of noncompacted to compacted myocardium .2:1; and color Doppler evidence of flow within the deep recesses affecting mainly the inferior and lateral walls [61,62] (Figure 17.13). However, even if these criteria appear sensitive, they lack specificity especially in the setting of systolic dysfunction. Other findings include reduced global left ventricular systolic function, diastolic dysfunction, left ventricular thrombi, and abnormal papillary muscle structure. Among patients with suggestive but not diagnostic findings, contrast echocardiography may help to establish the diagnosis by delineating the deep myocardial recesses [63]. CMR appears as a technique of great potential in the diagnostic approach of LVNC. Due to the wider field of view, the apical LV segments can be better delineated and the ratio of noncompacted to compacted myocardium accurately measured (Figure 17.13). A diastolic ratio of compacted over noncompacted myocardium of 2.3 measured

Multimodality Imaging in Cardiovascular Medicine

in diastole showed high diagnostic accuracy for distinguishing pathological LVNC from the degrees of noncompaction observed in healthy, dilated, and hypertrophied hearts [64]. The RV morphology together with associated cardiac abnormalities, the presence of thrombi on early gadolinium enhancement images, fibrosis on LGE imaging, and subendocardial perfusion defects suggestive of areas of microvascular dysfunction can be assessed as well in a single examination. The ability of contrast-enhanced CT to delineate the abnormal architecture of the LV wall with a high resolution associated to coronary imaging during the same scan has been reported in individual case reports (Figure 17.14).

Dilated Cardiomyopathy Dilated cardiomyopathy (DCM) is characterized by LV or biventricular dilatation and impaired contraction of 1 or both ventricles in the absence of an ischemic etiology. Noninvasive imaging plays a central role in accurate diagnosis, determination of etiology and prognosis, and in monitoring therapy. However, in up to 50% of DCM cases, the etiology remains unexplained. TTE defines in most cases the anatomic and functional characteristics of the heart that are diagnostic of dilated, hypertrophic, or restrictive cardiomyopathy. Thus, LV cavity dilatation with normal or decreased wall thickness, poor wall thickening, and impaired ejection fraction are commonly identifying features in DCM. Associated diastolic dysfunction, degree of filling pressures, RV dilatation and impairment, atrial enlargement, and valve regurgitation are easily depicted. Due to increased

F i g u r e 1 7 . 1 3 â•… Transthoracic echoÂ�cardiography and corresponding

carÂ�diovascular magnetic resonance images of a patient with suspected left ventricular (LV) noncompaction. Deep intertrabeculated recesses in communication with LV cavity in a patient with impaired systolic function suggestive of LV noncompaction. (Left) diastole, (right) systole.

F i g u r e 1 7 . 1 4 â•… Contrast-enhanced computed tomography delineating

with high resolution the deep left ventricular (LV) recesses fulfilling criteria for LV noncompaction. Courtesy of Dr L. Christiaens, Cardiologist, CHU Poitiers, France.

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wall stress, regional hypokinesia may be seen. Even if areas of myocardial thinning and akinesia or dyskinesia are suggestive of an ischemic etiology, tissue characterization and identification of the cause of a cardiomyopathy can be challenging with TTE. However, the high temporal resolution of echo Doppler offers the unique advantage of assessing and monitoring immediate changes in LV pressures and diastolic filling before and during treatment. Similarly, in the setting of DCM with refractory heart failure, mechanical dyssynchrony induced by conduction abnormalities can be measured using TDI modalities and Doppler, and their immediate correction can be guided and monitored during device implantation (eg, cardiac resynchronization therapy) (Figure 17.15). Residual contractile reserve, something of prognostic importance with regard to the potential for myocardial function recovery, can be easily assessed during stress echo with low doses of dobutamine. CCT appears to be an appealing tool to avoid invasive coronary angiography in low-risk patients presenting with

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a dilated cardiomyopathy to determine if there is an ischemic etiology. In a comparison study with coronary angiography, multidetector CT has been reported as safe, feasible, and accurate for detecting coronary artery disease with high sensitivity and specificity in DCM patients [65,66]. CMR is useful in providing accurate and reproducible assessment of ventricular volumes and mass with cine imaging. The location, distribution pattern, and extent of CMR LGE are often typical for a specific myocardial disorder, thus helping significantly in the differential diagnosis of a dilated heart with normal or reduced ejection fraction (Figure 17.16). LGE CMR can characterize areas of myocardial infarction signifying ischemic etiology. It also provides prognostic information in DCM. McCrohon et al have previously reported that subendocardial fibrosis indicative of a prior infarction is found in about 13% of DCM patients with a normal coronary angiogram, thus highlighting the potential for mid-diagnosis in this population, which may have important consequences regarding therapeutic decisions (aspirin, statins) and family screening

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F i g u r e 1 7 . 1 5 â•… Use of transthoracic echocardiography guided atrioventricular optimization in a patient with refractory heart failure after implantation of a biventricular pacemaker. The atrioventricular (AV) delay is lengthened to obtain an optimal filling of the left ventricle ((A) AV delay of 120 ms, there is no atrial filling; (B) AV delay lengthened to 200 ms resulting in a normalization of the filling pattern).

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1 7 . 1 6 â•…Distribution pattern and location of late gadolinium enhancement (LGE) help in the differential diagnosis of dilated cardiomyopathies. (A) Circumferential enhancement typical of amyloidosis. (B) Mid-wall fibrosis in the lateral wall in sarcoidosis. (C) Midwall LGE seen in dilated cardiomyopathy. (D) Subepicardial fibrosis linked to myocarditis. (E) Patchy fibrosis in hypertrophied areas in hypertrophic cardiomyopathy. (F) Typical subendocardial dense enhancement of a myocardial infarction. Figure

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(familial DCM) [24]. This also supports pathological data from explanted hearts of patients labeled as having a DCM and undergoing cardiac transplantation—a disproportionate percentage of this cohort transpire to have an ischemic basis. A further 28% of DCM patients in this study had a different pattern of LGE with mid-wall myocardial enhancement reflecting fibrosis and degeneration of myocytes in the circumferential fiber layer similar to autopsy findings (Figure 17.17). The presence of replacement fibrosis in DCM has been linked to increased risk of sudden cardiac death and ventricular arrhythmias independent of other more traditional markers of risk such as reduced LV ejection fraction [67,68]. The transmurality of fibrosis in DCM seems also related to increased likelihood of inducible ventricular tachycardia during electrophysiologic studies [69]. The accurate assessment of RV size and function by CMR is equally important in DCM as RV dilatation translates into a 3 times higher long-term mortality independent of the baseline LV ejection fraction [70]. Acquired Cardiomyopathies

Myocarditis (Inflammatory Cardiomyopathy) Myocarditis refers to an acute or chronic inflammatory process affecting the myocardium, resulting in necrosis or degeneration of myocytes. The most common etiologies include toxins, drugs, or infectious agents (most commonly viral). Clinical presentation is variable, ranging from flu-like symptoms to acute heart failure and sudden cardiac death. Despite standardized histologic criteria (the Dallas criteria), and availability of various histochemical analyses, the diagnosis remains challenging and the optimal prognostic classification system remains controversial. Although the majority of patients will recover spontaneously with complete recovery of LV function, a proportion will show progression to DCM. The ability to diagnose the disease and assess prognosis at the time of presentation is of great benefit in patients with myocarditis. Even if endomyocardial biopsy is recommended in case of suspected myocarditis, its diagnostic yield is limited by lack of sensitivity and false-negative results, in part due to the focal and transient nature of the infiltrates. TTE

1 7 . 1 7 â•… Typical mid-wall late gadolinium enhancement most marked in the septum in dilated cardiomyopathy. Figure

Multimodality Imaging in Cardiovascular Medicine

is generally the first imaging modality used at the bedside to detect decreased LV systolic function and quantify associated pericardial effusion. LV dysfunction is often global, but regional or segmental abnormalities may be present, mimicking an acute coronary syndrome. Some echocardiographic features have been suggested to be of diagnostic and prognostic value. Thus, LV size at presentation and wall thickness, as a marker of edema, appeared as distinctive factors between fulminant and acute myocarditis [71]. Transient increase in LV wall thickness and increased LV sphericity occur in acute stages of the disease. Detection of subtle diastolic dysfunction, reduced strain rate, and tissue velocities have been reported, increasing the diagnostic role of echocardiography [72]. Dobutamine echocardiography may be useful in the assessment of patients with recently diagnosed DCM, some of which may be caused by myocarditis, by demonstrating contractile reserve. However, most echocardiographic features remain nonspecific. Of the imaging approaches used to diagnose the disease, CMR has emerged as an important tool. In contrast to other diagnostic modalities, targets for CMR include several features of myocardial inflammation related to functional and morphological abnormalities as well as tissue pathology. At any stage of the disease, regional wall motion abnormalities and focal transient increases in wall thickness due to edema can be well visualized on CMR cine imaging. In the acute and early stages of the disease, increased cellular membrane permeability following lymphocytic infiltrate and myocytolysis increases the myocardial freewater content. T2-weighted imaging sensitively detects tissue edema, using the long T2 of water-bound protons as the contrast-generating mechanism resulting in a high signal intensity of edematous tissue. Tissue hyperemia, capillary leak, and increased distribution volume due to acute cell damage can be identified in the early phase, during the first minutes after gadolinium contrast injection, as an abnormal focal area of myocardial enhancement. Similarly, the pericardium may be enhanced if involved by the process. LGE mostly identifies irreversible myocardial necrosis [73]. In earlier stages of necrosis, however, cell membranes may be leaky and increase

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D F i g u r e 1 7 . 1 8 â•… Cardiovascular magnetic resonance images

of a viral myocarditis. T2-weighted sequences (A) displayed a thickened, edematous lateral wall (arrows). The corresponding late gadolinium enhancement (LGE) image (B) shows the localized areas of fibrosis (arrows), far less extensive than the edematous regions. In the early phase after Gadolinium injection (C), tissue hyperemia is seen as early enhancement, and the corresponding LGE image (D).

the volume of the interstitial compartment but be functionally intact. Thus, gadolinium molecules diffusing into the extracellular space will undergo a prolonged washout period. The diffusion of gadolinium into necrotic cells and the increased volume of distribution in the late washout period allow for using contrast-enhanced CMR to visualize inflammatory and necrotic changes during the acute phase of myocarditis. Foci of enhancement are typically located in the outer subepicardial myocardial layers, sparing the subendocardium in contrast to the enhancement pattern seen with myocardial infarction (Figure 17.18). The combined use of all 3 tissue-based parameters provides a good diagnostic accuracy for detection of myocarditis [74]. The exact localization of myocardial damage has been used to guide endomyocardial biopsy thus enhancing the diagnostic accuracy [74,75]. Even if the lateral wall is most frequently affected, other locations have been described and have been shown to correlate with differing viral etiologies. However, it is important to emphasize that the diagnosis of myocarditis cannot be established based on any clinical criteria or diagnostic modality alone, and findings have to be integrated into a comprehensive synopsis including history, clinical assessment, and test results. Secondary Cardiomyopathies

Amyloidosis Amyloidosis represents the extracellular deposition of fibrillar proteinaceous material in various organs and tissues in a variety of clinical settings. Cardiac involvement by amyloid fibril deposits represents the most important prognostic marker of the disease and occurs in up to 50% of patients with the type AL amyloidosis compared to less

than 5% with the AA type. Deposition of amyloid fibrils typically occurs in myocardial tissue, valve leaflets, interatrial septum, and myocardial vessels leading to luminal narrowing and potential arterial occlusion. Over time, these changes result in ventricular wall thickening and reduced compliance progressing to a restrictive cardiomyopathy. Clinical manifestations may be absent or range from right- or left-sided heart failure to ischemic stroke or syncope. Treatment options for symptomatic cardiac amyloidosis are limited, and most are ineffective, especially since cardiac involvement is typically identified only at the late stage. Treatments targeted at the early disease manifestations may, however, lead to a better outcome. In addition, other potentially curable conditions that amyloidosis may mimic should be excluded to guide management. The invasive aspect of myocardial biopsy has led in practice to the use of alternative noninvasive techniques. TTE typically displays LV wall thickening and LV and RV diastolic dysfunction in the earliest stage of the disease [76]. In more advanced stages, wall thickening progresses resulting in a small cavity sized LV associated with dilated atria, thickening of valve leaflets and the RV free wall, with variable degrees of pericardial and pleural effusions. Doppler evaluation of transmitral flow shows a restrictive filling pattern (Figure 17.19). Although the increased echogenicity of the heart (speckled appearance) has been described as a consequence of amyloid infiltration, only a minority of patients demonstrate this pattern and not typically in early disease. The combination of standard TTE assessment with tissue Doppler parameters allows for the distinction between amyloidosis and other hypertrophic cardiomyopathies, by displaying the typical marked dissociation between short-axis and long-axis systolic function. Thus, although LV ejection fraction is within normal range,

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F i g u r e 1 7 . 1 9 â•… Transthoracic echocardiography displaying typi-

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cal features of cardiac amyloidosis including a small left ventricular (LV) cavity size with thickened, hyperechogenic LV walls (A and B). The reduction in long-axis function is associated with a restrictive filling pattern (C) predominance of early LV filling, E wave with short deceleration time).

long-axis deformation (strain) and contraction (strain rate) are markedly reduced [77]. Myocardial contrast echo has been suggested as a way to detect associated microvascular dysfunction [78]. Although similar morphological abnormalities can be identified on CMR such as LV and RV wall thickening, atrial wall and valve leaflets thickening, and pleural and pericardial effusion, CMR excels in diagnosing the macroscopic changes of myocardial tissue composition induced by amyloidosis by the typical LGE CMR pattern not seen in any other hypertrophic disease [79]. This is particularly helpful in cases of cardiac amyloidosis (55% of cases) presenting with asymmetrical septal hypertrophy mimicking HCM. In the early phase after gadolinium contrast injection, intracardiac thrombi can be identified, typically in the left atrium or left atrial appendage (30% of AL amyloid patients). LGE in amyloidosis reflects interstitial expansion by amyloid fibrils and appears as a widespread enhancement mostly of the subendocardium matching the distribution of amyloid protein. Characteristically, LGE images are technically challenging to acquire with a very fast washout related to gadolinium kinetics of distribution into the total amyloid load. LGE imaging, therefore, typically shows a dark blood pool with global subendocardial late enhancement. Because the

mid-wall is relatively spared in the ventricular septum, there may be a characteristic zebra pattern with circumferential subendocardial enhancement of the LV and RV endocardium (Figure 17.20). Location of LGE abnormalities may also help guide endomyocardial biopsies [80].

Sarcoidosis Sarcoidosis is a multisystem granulomatous disease of unknown etiology that can affect all parts of the body (commonly lymph nodes and lungs). It can be a benign, incidentally discovered condition or a life-threatening disorder. Clinical evidence of myocardial involvement is present in approximately 5% of patients with sarcoidosis, although autopsy studies indicate that subclinical cardiac involvement is present in 20% to 30% of cases [81]. Myocardial involvement is common in patients with sarcoidosis who have cardiac symptoms (84% vs. 4% in asymptomatic) [82]. Pathological features of cardiac sarcoidosis include patchy infiltration of the myocardium evolving in 3 successive histological stages: edema, noncaseating epithelioid granulomatous infiltration, and fibrosis leading to postinflammatory scarring. Presenting features are those of conduction abnormalities, heart failure, and fatal ventricular arrhythmias.

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Due to their largely nonspecific nature, diagnostic tests such as endomyocardial biopsy and noninvasive imaging are required. Although the finding of noncaseating granulomas is diagnostic, a negative biopsy does not exclude the diagnosis due to its low sensitivity. TTE may document sequelae of cardiac sarcoidosis but cannot definitely exclude or establish the diagnosis. Thus, localized hyperechogenic areas in the septum or lateral wall can suggest granulomatous involvement. Ventricular aneurysms, valvular regurgitation, mitral valve prolapse due to papillary muscle dysfunction, left ventricular dilatation, or segmental or global hypokinesia of the left ventricle can all be detected as a consequence of the disease [83]. 201 Thallium scintigraphy myocardial perfusion studies typically show segmental areas of decreased uptake in the ventricular myocardium that disappear or decrease in size during stress or after intravenous administration of dipyridamole. However, this reverse distribution is not specific for cardiac sarcoidosis as it may also occur in other cardiomyopathies. 18 FDG PET has been shown to be useful for demonstration of both cardiac and extracardiac sarcoid disease [84] demonstrating areas of increased uptake (usually basal to mid anteroseptal and lateral wall) reducing in size or disappearing after steroid therapy. In the settings of suspected sarcoidosis, CMR appears promising for the early diagnosis and monitoring of the disease response to treatment. Owing to the large field of view, mediastinal lymphadenopathy and lung involvement can be imaged (Figure 17.21). Cine imaging depicts subtle regional wall motion abnormality. Focal areas of myocardial inflammation and edema due to sarcoid infiltrates are visible on T2-weighted and STIR imaging as localized hyperintense regions. Scarring and necrosis can

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magnetic resonance features of amyloidosis: (A) demonstrates a large pleural effusion (arrowhead) and a small pericardial effusion (arrow) with small-sized LV and hypertrophied walls. In the early phase after Gadolinium contrast injection, a left atrial appendage thrombus can be seen (B). (C–E) shows the typical late gadolinium enhancement circumferential zebra pattern of enhancement.

be detected on LGE images, typically patchy, with a midwall or subepicardial location and involving frequently the anteroseptal and anterolateral walls (Figure 17.21). Small myocardial lesions missed by other imaging modalities can be detected on LGE images, allowing for earlier diagnosis and treatment. Furthermore, LGE may guide endomyocardial biopsy and be used for steroid treatment monitoring [85–88]. Demonstration of early myocardial involvement can provide novel criteria for risk stratification for sudden cardiac death and heart failure. However, the LGE pattern is nonspecific and can be also found in other myocardial disorders such as myocarditis, and the predictive value of a negative CMR remains unknown.

Iron-Overload Cardiomyopathy Increased deposition of iron in the heart either as a result of excess dietary absorption (hereditary hemochromatosis) or from repeated blood transfusions leads to heart failure with systolic and/or diastolic dysfunction. The most striking model of iron-overload cardiomyopathy is seen in thalassemia major in which heart failure remains the major cause of death despite iron-chelating therapy. This form of cardiomyopathy is reversible, but intensive and effective iron chelation is necessary to remove myocardial iron. Myocardial iron content cannot be predicted reliably by serum ferritin or liver iron concentrations on biposy, and conventional assessment of cardiac function using TTE can only detect those with advanced disease. The emergence of CMR has made possible accurate measurements of both liver and cardiac iron in the same study. Its reproducibility and reliability offer a unique opportunity to monitor the effects of chelation therapy. Thus, iron levels

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1 7 . 2 1 â•… Bilateral hilar lymphÂ� adenopathy (A, arrow) Mid-wall fibrosis (B) and active inflammation (C) of the basal inferolateral wall are seen in a patient with biopsy-proven cardiac sarcoidosis. Figure

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F i g u r e 1 7 . 2 2 â•… Myocardial iron overload with typical epicardial iron deposition seen at a T2* of 12 ms: (A–C) acquired at different echo times from 2 ms to 14 ms, (D) example of a signal decay graph.

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are quantified from the image signal intensity or the calculated T2 relaxation time (T2*). Myocardial T2* arises principally from local magnetic field inhomogeneities that are increased with greater iron deposition. The typical epicardial deposition of iron noted at autopsy can be visualized in vivo by gradient echo images by acquiring a single short-axis midventricular slice at 9 separate echo times to derive the T2* value (Figure 17.22). Myocardial signal intensities are measured in the ventricular septum for each image and plotted against the echo time to form an exponential decay curve. Normal accepted values for the T2* of the myocardium at 1.5 T field strength are 33.3  7.8 milliseconds. The threshold of less than 10 milliseconds is used as indicative of severe iron loading. A T2* of 10 to 20 milliseconds corresponds to mild to moderate loading and more than 20 milliseconds to normal [89] The degree of myocardial iron is directly correlated to the degree of LV dysfunction. Therefore, T2* has been used as a predictive marker of heart failure and arrhythmias, and also to direct treatment and monitor the efficacy of chelation therapy, resulting in 80% reduction in mortality rates for this condition in the United Kingdom [89].

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Anderson-Fabry Disease Anderson-Fabry disease is an uncommon X-linked lysosomal storage disorder caused by alpha-galactosidase A deficiency. Progressive accumulation of globotriaosylceramide in various cells and organs leads to the manifestations of the disease. Although variability exists, the symptoms of Fabry’s disease tend to appear in a predictable order in classically affected males, including neurological, cutaneous, and renal manifestations during childhood followed by cardiac and cerebral involvement in adulthood [90]. Cardiac involvement including concentric LV hypertrophy, probably secondary to glycosphingolipid deposition within myocytes, is an early finding correlating with the severity of the disease. As an increase in LV wall thickness can be the only manifestation of the disease, Fabry’s disease should be considered in the differential diagnosis in patients with unexplained LV hypertrophy and late onset hypertrophic cardiomyopathy. The diagnosis can be suspected on TTE in patients with concentric LV hypertrophy of unknown etiology, associated with a binary appearance of the LV endocardial border (a thickened hyperechogenic layer in the subendocardium representing intracellular glycolipid deposition and a parallel hypoechogenic layer all along the ventricular contour representing the mildly affected mid-wall), absent in HCM and hypertensive patients [91]. Aortic and mitral valve regurgitation secondary to valve thickening can be seen as well as aortic root dilatation, but these signs are highly nonspecific. Among patients with known Fabry’s disease, TDI can provide a preclinical

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1 7 . 2 3 â•… Transthoracic echocardiography findings in Anderson-Fabry’s disease. Concentric LV hypertrophy (A) with localized area of reduced radial deformation (B: reduced radial strain, arrow) and contractility (C: reduced strain rate, arrow) in areas of fibrosis of the basal inferolateral wall. Figure

diagnosis of cardiac involvement, even in patients without LVH, and represent a sensitive tool for the assessment of cardiac improvement during enzyme replacement therapy [92]. The typical patterns of segmental deformation

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F i g u r e 1 7 . 2 4 â•…Anderson-Fabry’s disease. Corresponding Cardiovascular magnetic resonance images with concentric increase in left ventricular wall thickness (A–C, double arrows) with typical mid-wall fibrosis (D–E, arrow head), sparing the subendocardium in the basal inferolateral wall.

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and contraction as assessed by tissue Doppler strain and strain rate help the differential diagnosis of the various forms of hypertrophic heart disease (HCM, Â�hypertensive, infiltrative) (Figure 17.23). Moon et al reported that 50% of patients with Â�genetically confirmed Fabry’s disease have myocardial enhancement on CMR, generally observed in the basal inferolateral wall sparing the subendocardium [93] (Figure 17.24). This suggests that in addition to the accumulation of sphingolipid within myocytes, myocardial fibrosis also accounts for the extent of myocardial abnormalities seen. The pattern of LGE, different to that seen in HCM, is, therefore, of value in the diagnostic approach. Moreover, the presence of fibrosis as detected by LGE appears to be linked to less short- and long-term improvement with enzyme replacement therapy [94].

jâ•…C ONCLUSIONS The investigations of patients with heart failure have dramatically changed with the advent of powerful noninvasive modalities. Besides providing accurate morphological and functional information, the combination of several techniques allows preclinical detection of the disease and reproducible follow-up under treatment. The ability to characterize pathological tissue noninvasively provides new insights into the differential diagnosis of cardiomyopathies and risk stratification.

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jâ•…REFE RENCES â•‡ 1. Maron BJ, Towbin JA, Thiene G, et al. American Heart Association; Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; Council on Epidemiology and Prevention. Contemporary definitions and classification of the cardiomyopathies: an American Heart Association Scientific Statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; and Council on Epidemiology and Prevention. Circulation. 2006;113:1807–1816. â•‡ 2. Cerqueira MD, Weissman NJ, Dilsizian V, et al. Standardized myocardial segmentation and nomenclature for tomographic imaging of the heart: a statement for healthcare professionals from the Cardiac Imaging Committee of the Council on Clinical Cardiology of the American Heart Association. Circulation. 2002;105:539–542. â•‡ 3. Lang RM, Bierig M, Devereux RB, et al. Recommendations for chamber quantification: a report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr. 2005;18:1440–1463. â•‡ 4. Kirkpatrick JN, Lang RM. Heart failure: hemodynamic assessment using echocardiography. Curr Cardiol Rep. 2008;10:240–246. â•‡ 5. Oh JK, Hatle L, Tajik AJ, Little WC. Diastolic heart failure can be diagnosed by comprehensive two-dimensional and Doppler echocardiography. J Am Coll Cardiol. 2006;47:500–506. â•‡ 6. Jacob R, Stewart WJ. A practical approach to the quantification of valvular regurgitation. Curr Cardiol Rep. 2007;9:105–111. â•‡ 7. Wann S, Passen E. Echocardiography in pericardial disease. J Am Soc Echocardiogr. 2008;21:7–13. â•‡ 8. Alpert MA, Kelly DL, Value and limitations of echocardiography in the assessment of obese patients. Echocardiography. 2007;3:261–272.

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â•‡ 9. Naqvi TZ, Huynh HK. A new window of opportunity in echocardiography. J Am Soc Echocardiogr. 2006;19:569–577. 10. Leonardi B, Margossian R, Colan SD, Powell AJ. Relationship of magnetic resonance imaging estimation of myocardial iron to left ventricular systolic and diastolic function in thalassemia. JACC: Cardiovascular Imaging. 2008;1:572–578. 11. Trambaiolo P, Tonti G, Salustri A, Fedele F, Sutherland G. New insights into regional systolic and diastolic left ventricular function with tissue Doppler echocardiography: from qualitative analysis to a quantitative approach. J Am Soc Echocardiogr. 2001;14:85–96. 12. Nesbitt GC, Mankad S, Oh JK. Strain imaging in echocardiography: methods and clinical applications. Int J Cardiovasc Imaging. January 15, 2009. 13. Perk G, Tunick PA, Kronzon I. Non-Doppler two-dimensional strain imaging by echocardiography—from technical considerations to clinical applications. J Am Soc Echocardiogr. 2007;20:234–243. 14. Maceira AM, Prasad SK, Khan M, Pennell DJ. Normalized left ventricular systolic and diastolic function by steady state free precession cardiovascular magnetic resonance. J Cardiovasc Magn Reson. 2006;8:417–426. 15. Maceira AM, Prasad SK, Khan M, Pennell DJ. Reference right ventricular systolic and diastolic function normalized to age, gender and body surface area from steady-state free precession cardiovascular magnetic resonance. Eur Heart J. 2006;27:2879–2888. 16. Bello D, Shah DJ, Farah GM, et al. Gadolinium cardiovascular magnetic resonance predicts reversible myocardial dysfunction and remodeling in patients with heart failure undergoing beta-blocker therapy. Circulation. 2003;108:1945–1953. 17. Grothues F, Moon JC, Bellenger NG, Smith GS, Klein HU, Pennell DJ. Interstudy reproducibility of right ventricular volumes, function, and mass with cardiovascular magnetic resonance. Am Heart J. 2004;147:218–223. 18. Westwood MA, Anderson LJ, Maceira AM, et al. Normalized left ventricular volumes and function in thalassemia major patients with normal myocardial iron. J Magn Reson Imaging. 2007; 25:1147–1151. 19. Westwood M, Anderson LJ, Firmin DN, et al. A single breath-hold multiecho T2* cardiovascular magnetic resonance technique for diagnosis of myocardial iron overload. J Magn Reson Imaging. 2003;18:33–39. 20. Caruthers SD, Lin SJ, Brown P, et al. Practical value of cardiac magnetic resonance imaging for clinical quantification of aortic valve stenosis: comparison with echocardiography. Circulation. 2003;108:2236–2243. 21. Ambrosi P, Habib G, Ferracci A, Faugère G, Luccioni R, Bernard PJ. Quantification of mitral regurgitation by cine-MRI. Comparison with transesophageal echocardiography in 45 patients. Arch Mal Coeur Vaiss. 1997;90:1463–1467. 22. Rademakers FE, Bogaert J. Cardiac dysfunction in heart failure with normal ejection fraction: MRI measurements. Prog Cardiovasc Dis. 2006;49:215–227. 23. Assomull RG, Prasad SK, Lyne J, et al. Cardiovascular magnetic resonance, fibrosis, and prognosis in dilated cardiomyopathy. Am Coll Cardiol. 2006;48:1977–1985. 24. McCrohon JA, Moon JC, Prasad SK, et al. Differentiation of heart failure related to dilated cardiomyopathy and coronary artery disease using gadolinium-enhanced cardiovascular magnetic resonance. Circulation. 2003;108:54–59. 25. Rist C, Johnson TR, Becker CR, Reiser MF, Nikolaou K. New applications for noninvasive cardiac imaging: dual-source computed tomography. Eur Radiol. 2007;17(suppl 6):F16–F25. 26. Lembcke A, Wiese TH, Enzweiler CN, et al. Quantification of mitral valve regurgitation by left ventricular volume and flow measurements using electron beam computed tomography: comparison with magnetic resonance imaging. J Comput Assist Tomogr. 2003;27:385–391. 27. Lembcke A, Borges AC, Dushe S, et al. Assessment of mitral valve regurgitation at electron-beam CT: comparison with Doppler echocardiography. Radiology. 2005;236:47–55.

2 81

28. Aguilar F, Nesser HJ, Faletra F, et al. Imaging modalities in valvular heart disease. Curr Cardiol Rep. 2008;10:98–103. 29. Cawley PJ, Maki JH, Otto CM. Cardiovascular magnetic resonance imaging for valvular heart disease: technique and validation. Circulation. 2009;119:468–478. 30. Chun EJ, Choi SI, Lim C, et al. Aortic stenosis: evaluation with multidetector CT angiography and MR imaging. Korean J Radiol. 2008;9:439–448. 31. Masci PG, Dymarkowski S, Bogaert J. Valvular heart disease: what does cardiovascular MRI add? Eur Radiol. 2008;18:197–208. 32. Oudkerk M, Stillman AE, Halliburton SS, et al. Coronary artery calcium screening: current status and recommendations from the European Society of Cardiac Radiology and North American Society for Cardiovascular Imaging. Eur Radiol. 2008;18:2785–2807. 33. Elkeles RS, Godsland IF, Feher MD, et al; for the PREDICT Study Group. Coronary calcium measurement improves prediction of cardiovascular events in asymptomatic patients with type 2 diabetes: the PREDICT study. Eur Heart J. 2008;29:2244–2251. 34. Miller JM, Rochitte CE, Dewey M, et al. Diagnostic performance of coronary angiography by 64-row CT. N Engl J Med. 2008;359:2324–2336. 35. Gemayel C, Pelliccia A, Thompson PD. Arrhythmogenic right ventricular cardiomyopathy. J Am Coll Cardiol. 2001;38:1773–1781. 36. Sen-Chowdhry S, Syrris P, Ward D, Asimaki A, Sevdalis E, McKenna WJ. Clinical and genetic characterization of families with arrhythmogenic right ventricular dysplasia/cardiomyopathy provides novel insights into patterns of disease expression. Circulation. 2007;115:1710–1720. 37. Corrado D, Fontaine G, Marcus FI, et al; for the Study Group on Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy of the Working Groups on Myocardial and Pericardial Disease and Arrhythmias of the European Society of Cardiology and of the Scientific Council on Cardiomyopathies of the World Heart Federation. Arrhythmogenic right ventricular dysplasia/cardiomyopathy: need for an international registry. Circulation. 2000;101:e101–e106. 38. Kjaergaard J, Hastrup Svendsen J, Sogaard P, et al. Advanced quantitative echocardiography in arrhythmogenic right ventricular cardiomyopathy. J Am Soc Echocardiogr. 2007;20:27–35. 39. Prakasa KR, Wang J, Tandri H, et al. Utility of tissue Doppler and strain echocardiography in arrhythmogenic right ventricular dysplasia/cardiomyopathy. Am J Cardiol. 2007;100:507–512. 40. Sen-Chowdhry S, Prasad SK, Syrris P, et al. Cardiovascular magnetic resonance in arrhythmogenic right ventricular cardiomyopathy revisited: comparison with task force criteria and genotype. J Am Coll Cardiol. 2006;48:2132–2140. 41. Nijveldt R, Germans T, van Rossum AC. Role of magnetic resonance imaging in arrhythmogenic right ventricular cardiomyopathy. Am Heart J. 2008;155:e57. 42. Burke AP, Farb A, Tashko G, Virmani R. Arrhythmogenic right ventricular cardiomyopathy and fatty replacement of the right ventricular myocardium: are they different diseases? Circulation. 1998;97:1571–1580. 43. Tandri H, Saranathan M, Rodriguez ER, et al. Noninvasive detection of myocardial fibrosis in arrhythmogenic right ventricular cardiomyopathy using delayed-enhancement magnetic resonance imaging. J Am Coll Cardiol. 2005;45:98–103. 44. Sen-Chowdhry S, Syrris P, Ward D, Asimaki A, Sevdalis E, McKenna WJ. Clinical and genetic characterization of families with arrhythmogenic right ventricular dysplasia/cardiomyopathy provides novel insights into patterns of disease expression. Circulation. 2007;115:1710–1720. 45. Kimura F, Sakai F, Sakomura Y, et al. Helical CT features of arrhythmogenic right ventricular cardiomyopathy. Radiographics. 2002;22:1111–1124. 46. Maron BJ, Gardin JM, Flack JM, Gidding SS, Kurosaki TT, Bild DE. Prevalence of hypertrophic cardiomyopathy in a general population of young adults: echocardiographic analysis of 4111 subjects in a CARDIA study. Circulation. 1995;92:785–789. 47. Maron BJ. Sudden death in young athletes. N Engl J Med. 2003; 349:1064–1075.

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48. Baltabaeva A, Marciniak M, Bijnens B, et al. Regional left ventricular deformation and geometry analysis provides insights in myocardial remodelling in mild to moderate hypertension. Eur J Echocardiogr. 2008;9:501–508. 49. Moon JC, Fisher NG, McKenna WJ, Pennell DJ. Detection of apical hypertrophic cardiomyopathy by cardiovascular magnetic resonance in patients with non-diagnostic echocardiography. Heart. 2004;90:645–649. 50. Rickers C, Wilke NM, Jerosch-Herold M, et al. Utility of cardiac magnetic resonance imaging in the diagnosis of hypertrophic cardiomyopathy. Circulation. 2005; 112:855–861. 51. Moon JC, McKenna WJ, McCrohon JA, Elliott PM, Smith GC, Pennell DJ. Toward clinical risk assessment in hypertrophic cardiomyopathy with gadolinium cardiovascular magnetic resonance. J Am Coll Cardiol. 2003;41:1561–1567. 52. Adabag AS, Maron BJ, Appelbaum E, et al. Occurrence and frequency of arrhythmias in hypertrophic cardiomyopathy in relation to delayed enhancement on cardiovascular magnetic resonance. J Am Coll Cardiol. 2008;51:1369–1374. 53. Suk T, Edwards C, Hart H, Christiansen JP. Myocardial scar detected by contrast-enhanced cardiac magnetic resonance imaging is associated with ventricular tachycardia in hypertrophic cardiomyopathy patients. Heart Lung Circ. 2008;17:370–374. 54. Kwon DH, Setser RM, Popović ZB, et al. Association of myocardial fibrosis, electrocardiography and ventricular tachyarrhythmia in hypertrophic cardiomyopathy: a delayed contrast enhanced MRI study. Int J Cardiovasc Imaging. 2008;24:617–625. 55. Petersen SE, Jerosch-Herold M, Hudsmith LE, et al. Evidence for microvascular dysfunction in hypertrophic cardiomyopathy: new insights from multiparametric magnetic resonance imaging. Circulation. 2007;115:2418–2425. 56. Ishida Y, Nagata S, Uehara T, Yasumura Y, Fukuchi K, Miyatake K. Clinical analysis of myocardial perfusion and metabolism in patients with hypertrophic cardiomyopathy by single photon emission tomography and positron emission tomography. J Cardiol. 2001;37(suppl 1):121–128. 57. Lorenzoni R, Gistri R, Cecchi F, et al. Coronary vasodilator reserve is impaired in patients with hypertrophic cardiomyopathy and left ventricular dysfunction. Am Heart J. 1998;136:972–981. 58. Mitsutake R, Miura S, Sako H, Nishikawa H, Saku K. Usefulness of multi-detector row computed tomography for the management of percutaneous transluminal septal myocardial ablation in patient with hypertrophic obstructive cardiomyopathy. Int J Cardiol. 2008;129:e61–e63. 59. Burke A, Mont E, Kutys R, Virmani R. Left ventricular noncompaction: a pathological study of 14 cases. Hum Pathol. 2005; 36:408–411. 60. Jenni R, Oechslin EN, van der Loo B. Isolated ventricular non-compaction of the myocardium in adults. Heart. 2007; 93:11–15. 61. Chin TK, Perloff JK, Williams RG, Jue K, Mohrmann R. Isolated noncompaction of left ventricular myocardium. A study of eight cases. Circulation. 1990;82:507–513. 62. Jenni R, Oechslin E, Schneider J, Attenhofer Jost C, Kaufmann PA. Echocardiographic and pathoanatomical characteristics of isolated left ventricular non-compaction: a step towards classification as a distinct cardiomyopathy. Heart. 2001;86:666–671. 63. De Groot-de Laat LE, Krenning BJ, ten Cate FJ, Roelandt JR. Usefulness of contrast echocardiography for diagnosis of left ventricular noncompaction. Am J Cardiol. 2005; 95:1131–1134. 64. Petersen SE, Selvanayagam JB, Wiesmann F, et al. Left ventricular non-compaction: insights from cardiovascular magnetic resonance imaging. J Am Coll Cardiol. 2005; 46:101–105. 65. Ghostine S, Caussin C, Habis M, et al. Non-invasive diagnosis of ischemic heart failure using 64-slice computed tomography. Eur Heart J. 2008;29:2133–2140. 66. Andreini D, Pontone G, Pepi M, et al. Diagnostic accuracy multidetector computed tomography coronary angiography in patients with dilated cardiomyopathy. J Am Coll Cardiol. 2007;49:2044–2050.

67. Assomull RG, Prasad SK, Lyne J, et al. Cardiovascular magnetic resonance, fibrosis, and prognosis in dilated cardiomyopathy. J Am Coll Cardiol. 2006;48:1977–1985. 68. Wu KC, Weiss RG, Thiemann DR, et al. Late gadolinium enhancement by cardiovascular magnetic resonance heralds an adverse prognosis in nonischemic cardiomyopathy. J Am Coll Cardiol. 2008;51:2414–2421. 69. Nazarian S, Bluemke DA, Lardo AC, et al. Magnetic resonance assessment of the substrate for inducible ventricular tachycardia in nonischemic cardiomyopathy. Circulation. 2005;112:2821–2825. 70. Sun JP, James KB, Yang XS, et al. Comparison of mortality rates and progression of left ventricular dysfunction in patients with idiopathic dilated cardiomyopathy and dilated versus non-dilated right ventricular cavities. Am J Cardiol. 1997;80:1583–1587. 71. Felker GM, Boehmer JP, Hruban RH, et al. Echocardiographic findings in fulminant and acute myocarditis. J Am Coll Cardiol. 2000;36:227–232. 72. Skouri HN, Dec GW, Friedrich MG, Cooper LT. Noninvasive imaging in myocarditis. J Am Coll Cardiol. 2006;48:2085–2093. 73. Mahrholdt H, Goedecke C, Wagner A, et al. Cardiovascular magnetic resonance assessment of human myocarditis: a comparison to histology and molecular pathology. Circulation. 2004;109:1250–1258. 74. Abdel-Aty H, Boyé P, Zagrosek A, et al. Diagnostic performance of cardiovascular magnetic resonance in patients with suspected acute myocarditis: comparison of different approaches. J Am Coll Cardiol. 2005;45:1815–1822. 75. Mahrholdt H, Goedecke C, Wagner A, et al. CMR assessment of human myocarditis: a comparison to histology and molecular pathology. Circulation. 2004; 109:1250–1258. 76. Klein AL, Hatle LK, Burstow DJ, et al. Comprehensive Doppler assessment of right ventricular diastolic function in cardiac amyloidosis. J Am Coll Cardiol. 1990;15:99–108. 77. Koyama J, Ray-Sequin PA, Falk RH. Longitudinal myocardial function assessed by tissue velocity, strain, and strain rate tissue Doppler echocardiography in patients with AL (primary) cardiac amyloidosis. Circulation. 2003;107:2446–2452. 78. Abdelmoneim SS, Bernier M, Bellavia D, et al. Myocardial contrast echocardiography in biopsy-proven primary cardiac amyloidosis. Eur J Echocardiogr. 2008;9:338–341. 79. Maceira AM, Joshi J, Prasad SK, et al. Cardiovascular magnetic resonance in cardiac amyloidosis. Circulation. 2005;111:186–193. 80. Vogelsberg H, Mahrholdt H, Deluigi CC, et al. Cardiovascular Â�magnetic resonance in clinically suspected cardiac amyloidosis: noninvasive imaging compared to endomyocardial biopsy. J Am Coll Cardiol. 2008;51:1022–1030. 81. Virmani R, Bures JC, Roberts WC. Cardiac sarcoidosis; a major cause of sudden death in young individuals. Chest. 1980;77:423–428. 82. Smedema JP, Snoep G, van Kroonenburgh MP, et al. Cardiac involvement in patients with pulmonary sarcoidosis assessed at two university medical centers in the Netherlands. Chest. 2005;128:30–35. 83. Fahy GJ, Marwick T, McCreery CJ, Quigley PJ, Maurer BJ. Doppler echocardiographic detection of left ventricular diastolic dysfunction in patients with pulmonary sarcoidosis. Chest. 1996;109:62–66. 84. Mana J. Nuclear imaging. 67Gallium, 201thallium, 18F-labeled fluoro-2-deoxy-D-glucose positron emission tomography. Clin Chest Med. 1997;18:799–811. 85. Smedema JP, Snoep G, van Kroonenburgh MP, et al. Evaluation of the accuracy of gadolinium-enhanced cardiovascular magnetic resonance in the diagnosis of cardiac sarcoidosis. J Am Coll Cardiol. 2005;45:1683–1690. 86. Osman F, Foundon A, Leyva P, Pitt M, Murray RG. Early diagnosis of cardiac sarcoidosis using magnetic resonance imaging. Int J Cardiol. 2008;125:e4–e5. 87. Borchert B, Lawrenz T, Bartelsmeier M, Röthemeyer S, Kuhn H, Stellbrink C. Utility of endomyocardial biopsy guided by delayed enhancement areas on magnetic resonance imaging in the diagnosis of cardiac sarcoidosis. Clin Res Cardiol. 2007; 96:759–762.

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88. Shimada T, Shimada K, Sakane T, et al. Diagnosis of cardiac Â�sarcoidosis and evaluation of the effects of steroid therapy by Â�gadolinium-DTPA-enhanced magnetic resonance imaging. Am J Med. 2001;110:520–527. 89. Anderson LJ, Holden S, Davis B, et al. Cardiovascular T2-star (T2*) magnetic resonance for the early diagnosis of myocardial iron overload. Eur Heart J. 2001; 22:2171–2179. 90. MacDermot KD, Holmes A, Miners AH. Anderson-Fabry disease: clinical manifestations and impact of disease in a cohort of 98 hemizygous males. J Med Genet. 2001;38:750–760. 91. Pieroni M, Chimenti C, De Cobelli F, et al. Fabry’s disease cardiomyopathy: echocardiographic detection of endomyocardial glycosphingolipid compartmentalization. J Am Coll Cardiol. 2006;47:1663–1671.

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92. Toro R, Perez-Isla L, Doxastaquis G, et al. Clinical usefulness of tissue Doppler imaging in predicting preclinical Fabry cardiomyopathy. Int J Cardiol. 2009;132(1):38–44. 93. Moon JC, Sachdev B, Elkington AG, et al. Gadolinium enhanced cardiovascular magnetic resonance in Anderson-Fabry disease. Evidence for a disease specific abnormality of the myocardial interstitium. Eur Heart J. 2003;24:2151–2155. 94. Weidemann F, Niemann M, Breunig F, et al. Long-term effects of enzyme replacement therapy on Fabry cardiomyopathy: evidence for a better outcome with early treatment. Circulation. 2009;119:524–529.

18

Multimodality Imaging in Atrial Arrhythmias

e Wa De mBoWSKi jo SePH A. L o daTo Am iT r. PaT el

Advances in technology and in the understanding of the pathophysiology of various atrial arrhythmias, especially atrial fibrillation (AF), have led to more definitive and potentially curative therapeutic approaches. Critical to these approaches is a thorough evaluation of atrial anatomy and function as well as its surrounding anatomical structures requiring the use of multimodality imaging. Although atrial anatomy was described more than a century ago, a new interest in atrial anatomy and its relationship with atrial electromechanical function has emerged due to catheter ablation procedures. Echocardiography has a well-established role in the initial assessment of patients with atrial arrhythmias. In recent years, cardiac magnetic resonance (CMR) and multidetector computed tomography (MDCT) have contributed significantly to a better understanding of cardiac anatomy and function. In addition, image fusion between electroanatomical mapping and these modalities has enabled the integration of anatomy and electrophysiological function to guide percutaneous interventions. This chapter describes the use of multimodality imaging in the evaluation, treatment, and follow-up of patients with atrial arrhythmias. Although potentially generalizable to other atrial arrhythmias, the chapter focuses on AF where cardiac imaging is critical in all stages of management, especially if treatment involves catheter ablation procedures. jâ•…P REPROCEDURAL IMAGING Initial Assessment With Echocardiography As part of the initial evaluation, all patients with AF should undergo imaging to exclude potential underlying causes, such as clinically silent valvular, myocardial, pericardial, and congenital heart disease. Treatment of these conditions may revert AF and maintain sinus rhythm. In addition, information gathered from initial cardiac 284

imaging can guide the choice of subsequent management strategies. The imaging modality of choice for the initial assessment is transthoracic echocardiography (TTE). Guidelines recommend that all patients with a first episode of AF should undergo TTE to establish structural abnormalities as well as to measure baseline left atrial (LA) size, left ventricular (LV) dimensions, LV wall thickness, and LV function [1,2]. LV systolic dysfunction, LV diastolic dysfunction, LV hypertrophy, and enlarged LA size have been shown to be independent predictors of nonvalvular AF [3]. The mechanism involved in these clinical settings is increased LV filling pressure leading to LA enlargement and subsequent AF. LV pressure in AF can be estimated by Doppler and tissue Doppler imaging (TDI) in TTE. In normal sinus rhythm, the transmitral flow velocity pattern measured by Doppler is composed of an early transmitral velocity, called the E wave, followed by a later A wave, arising from atrial contraction. In AF, because atrial contraction is lost, the transmitral flow does not exhibit an A wave. TDI records systolic and diastolic myocardial velocities by measuring the velocity of tissue motion in a sample region of interest. In normal sinus rhythm, the tissue Doppler velocity pattern of the mitral annulus is composed of an early diastolic velocity (E9) corresponding to the early filling phase, followed by late diastolic velocity from atrial contraction (A9). In AF, the mitral annular filling velocity pattern does not have an A9 wave. Combining the information obtained from Doppler and tissue Doppler allows for calculation of the E/E9 ratio. This ratio has been shown to reliably estimate LV filling pressures and predict prognosis (independently of LVEF) in patients with AF (Figure 18.1) [4,5]. Information gained from a TTE can influence the subsequent management strategies for a patient with AF. For example, a structurally normal heart may suggest a triggered mechanism for AF that may be amenable to catheter ablation. Appropriate patient selection for catheter ablation is important to optimize the success and safety of the procedure. The presence of LV systolic dysfunction can also guide the choice of pharmacological rate or rhythm control agents [1]. Certain antiarrhythmic drugs should be avoided

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F igure 1 8 . 1 â•…Measurement of E/e’ ratio in atrial fibrillation can reliably estimate left ventricular filling pressure. The panel on top left shows the

transmitral velocity in atrial fibrillation (E, early transmitral flow velocity). Tissue Doppler imaging in atrial fibrillation (e’, early diastolic mitral annular velocity) is shown on top right. The prognostic value of the E/e’ is demonstrated by the Kaplan-Meier plots. Adapted from Ref. 4.

in patients with structural heart disease, as there is an increased risk of adverse events in these patients. TTE can also guide long-term thromboembolic stroke reduction in patients with AF [1]. The presence of impaired LV function on TTE, for example, identifies a patient at high risk for a thrombotic event.

jâ•…A TRIAL THROMBI AND THROMBOEMBOLIC RISK Patients with AF are at increased risk for thrombus formation and cerebral embolism. Imaging with TTE can identify intracardiac thrombus as well as predict thromboembolic risk. Varying degrees of blood stasis have been described in patients with AF (Figure 18.2), ranging from spontaneous echocontrast (SEC), to sludge, to thrombus. SEC is visualized as echogenic swirling blood flow, reflecting red cell and clotting factor aggregation in the setting of low blood velocity. It is associated with development of thrombus and with systemic embolization [5,6]. Sludge is a viscid hyperechoic signal in the LA and left atrial appendage (LAA) without clear thrombus formation. Sludge represents thrombus in situ that is a stage further along in the continuum toward thrombus formation. The presence of LA, LAA thrombus, or

dense SEC is a marker for increased risk of stroke in patients with AF (17%) despite oral anticoagulation [7–10]. RAA thrombi have also been reported in patients with AF. This finding is uncommon and generally accompanied by LAA thrombus as well. The incidence of LA/ LAA and RA/RAA thrombus is 10% to 15% and 0.4% to 7.5%, respectively, in patients with AF [11]. Compared with TTE, multiplane transesophageal echocardiography (TEE) provides superior assessment of the LA and LAA in the majority of patients [12]. TEE can detect LAA thrombi with a high degree of sensitivity, specificity, and negative predictive value [13]. However, despite its high accuracy, TEE can be insensitive to thrombi ,2 mm, particularly in multilobed LA appendages. In addition, artifacts, pectinate muscles, and severe SEC are occasionally confused for thrombus. Although TEE is the standard technique to exclude LAA thrombus, several recent studies have reported the usefulness and limitations of MDCT in the assessment of LAA thrombus [14,15]. Contrast-enhanced MDCT can rule out a thrombus with a high negative predictive value [15]. However, concerns about the ability of MDCT to differentiate thrombus from SEC currently limits its use as a standard imaging modality. The finding of LA or LAA thrombus on TEE is an absolute contraindication for cardioversion or catheter

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F igure 1 8 . 2 â•…Thrombus in left atrial append-

age. (A) Thrombus in the left atrial appendage on transesophageal echocardiography; (B) Thrombus in the left atrial appendage on cardiac computed tomography; (C) Sludge is an intermediate stage of thrombosis characterized by precipitous, dense spontaneous echo contrast seen throughout the cardiac cycle; and (D) Pulsed-wave Doppler of the left atrium appendage emptying velocity measured at end diastole. Velocities ,20 cm/s are associated with spontaneous echo contrast and thrombus formation and increased likelihood of stroke.

ablation procedures and portends a poor outcome. In one study, it was associated with an embolic risk of up to 10% per year and a death risk of 16% in a series of patients, most of whom were receiving oral anticoagulation [16]. Patients with AF and dense SEC also have a high likelihood of cerebral embolism or death, despite oral anticoagulation [17]. Unlike thrombus, SEC in the LA or LAA is not an absolute contraindication to cardioversion or ablation, and oral anticoagulation with warfarin does not appear to influence it. During catheter ablation procedures, careful monitoring for LA thrombus is essential in the setting of SEC as this finding tends to increase catheter- and sheath-related thrombi [18]. Not all SEC is associated with the same risk; dense SEC seen throughout the cardiac cycle is associated with a poorer outcome than mild, intermittent SEC. Reduced or absent LAA velocities and low LAA ejection fractions are associated with SEC, thrombus formation, and systemic embolism [17]. LAA emptying velocities can be assessed with TEE using pulse wave Doppler with the sample volume 1 cm within the LAA. Low LAA emptying velocity (,20 cm/s) is a marker of poor LAA mechanical function and correlates strongly with the presence of SEC and thrombus formation [19–22]. Echocardiography may add information useful in stratifying thromboembolic risk. Among high-risk AF patients, LV dysfunction on TTE, thrombus, dense SEC, reduced velocity of blood flow in the LAA, and complex atheromatous plaque in the thoracic aorta on TEE have been associated with thromboembolism, and oral anticoagulation effectively lowers the risk of stroke in AF patients with these features [8,9]. However, these

parameters have not been shown to be independent predictors of stroke. Furthermore, whether the absence of these echocardiographic abnormalities identifies a lowrisk group of patients who could safely avoid anticoagulation has not been definitively established in a large cohort of patients, limiting the value of echocardiography as a prime determinant of the need for chronic anticoagulation in patients with AF.

jâ•…A TRIAL STRUCTURE AND FUNCTION Structural and functional changes in the LA contribute to local impairment of electrical conduction and to AF recurrences. These changes include LA enlargement, reduction in LA compliance, and development of LA fibrosis. Each has been evaluated as a predictor in the development of AF as well as a predictor of the success of maintenance of sinus rhythm after ablation or cardioversion of AF. jâ•…A TRIAL SIZE One important consideration in all patients with AF is determining LA size. LA enlargement is common in AF, particularly in patients with other structural heart diseases [23]. Sustained AF can lead to further increases in atrial dimensions, which can be reversible after conversion to normal sinus rhythm [24]. LA size has been shown to be incremental to clinical risk factors predicting AF in subsets of patients. LA size also provides prognostic value as to the success of a rhythm control strategy. LA enlargement decreases the probability of long-term

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F igure 1 8 . 3 â•… Left atrial (LA) volume. Using echocardiography (ECHO), LA volume can be determined by the biplane method of disks (modified Simpson’s rule) using the apical 4-chamber (A4C) and apical 2-chamber (A2C) views at ventricular end systole (maximum LA size). The Simpson’s rule states that the volume of a geometric figure can be calculated from the sum of the volumes of smaller figures of similar shape. The volume of the entire LA can be derived from the sum of the volume of the individual disks. The LA volume can be more precisely measured (with fewer geometric assumptions) using 3D ECHO, cardiac magnetic resonance, or multidetector computed tomography.

maintenance of sinus rhythm after successful electrical or pharmacological cardioversion [25,26]. Patients with prolonged AF and marked LA dilatation are also less likely to have a successful catheter ablation procedure than those with structurally normal hearts [27]. Current guidelines reflect this correlation and support catheter ablation as a reasonable alternative to pharmacologic therapy in symptomatic patients with little or no LA enlargement [1]. LA size can be measured as anteroposterior dimension on M-mode or 2-dimensional (2D) TTE in the parasternal long-axis view. Although this measurement has been used extensively in clinical and research work, it is now recognized as an inadequate estimation of the true LA size. The current recommendation is to measure biplane LA volume from the apical 4- and 2-chamber views, using the area length or Simpson’s formula (Figure 18.3) [28]. Compared with other imaging modalities, such as CT [29] and MRI [30], there is a tendency for echocardiographic measures to underestimate LA size. MRI is considered to be the gold standard for atrial volume measurements and has shown excellent correlation with right and LA cadaveric casts [31]. More recently, LA volume with 3-dimensional (3D) TTE was validated against MRI and appears to have more precision in measurement than that with 2D TTE [32].

jâ•…A TRIAL MECHANICAL FUNCTION LA mechanical function can be assessed by echocardiography. Transmitral pulse-wave Doppler as well as pulmonary and hepatic venous flow have been used to evaluate atrial function, but the shape of the spectral profile is dependent on a number of factors, in particular, heart rate and valve regurgitation. More recently, TDI has been used to assess regional atrial mechanical function by placing a sample

volume of interest in a basal or mid atrial segment. Strain and strain rate imaging are derived from these TDI velocities. Strain measures the myocardial deformation during a cardiac cycle, and strain rate measures the tissue velocity gradient within the myocardium. Measurements of strain and strain rate are independent of any translational effects due to tethering by neighboring myocardial segments and, therefore, are the preferred measurements to represent mechanical function. Studies of TDI and strain values demonstrate that LA mechanical function is significantly decreased in AF (Figure 18.4). Both atrial strain and strain rate appear to independently predict AF [33]. In addition, higher atrial strain and strain rate correlate with increased likelihood of remaining in sinus rhythm after successful cardioversion [33] and after catheter ablation [34]. Combining LA mechanical dysfunction with the degree of LA enlargement gives the strongest predictive value of AF recurrence following electrical cardioversion [35]. Measures of strain rate post successful cardioversion show gradual improvement of atrial mechanical function over time [36]. Transiently reduced atrial mechanical function after restoration of sinus rhythm from AF, termed atrial stunning, is the basis for the anticoagulation guidelines after cardioversion [24]. Atrial stunning has been documented for up to 4 weeks and has been described after spontaneous, pharmacological, and electrical cardioversion [6]. Although TDI imaging of the LAA has been described, its mechanical function is best assessed with TEE pulse wave Doppler filling velocities. As previously noted, low LAA emptying velocities (,20 cm/s) correlate strongly with the presence of SEC and thrombus formation [9]. In contrast, high LAA emptying velocities (.40 cm/s) have been shown to predict greater likelihood of sustained normal sinus rhythm 1 year after cardioversion [37].

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(A) Normal

TVI

Strain rate

Strain

(B) Atrial fibrillation

TVI

Strain rate

Strain

F igure 1 8 . 4 â•…Tissue Doppler imaging (TDI) demonstrates decreased atrial strain and atrial strain rate in patients with atrial fibrillation. TDI mea-

surements were obtained by placing the sample volume in the mid-segment of the left atrial septal wall. (AVC = aortic valve closure). The top panel (A) demonstrates typical TDI, strain rate, and strain seen in a normal patient. Significantly lower TDI velocities seen in a patient with atrial fibrillation (B). Both strain and strain rate are also decreased in patients with atrial fibrillation. Adapted from Ref. 34.

jâ•…A TRIAL REMODELING AF is a progressive and self-sustaining disease where chronic or recurrent fibrillatory activation induces progressive functional and structural remodeling, resulting in regions of low-voltage atrial tissue [38]. Histological examination of these low-voltage regions has shown the presence of fibrosis [39]. A recent study used late gadolinium enhancement magnetic resonance imaging (LGE-MRI) to noninvasively determine the extent and location of fibrosis in the LA (Figure 18.5) [40]. In this study, an increased amount of enhancement within the LA was found to be strongly associated with AF recurrence after catheter ablation. In addition, locations of LA enhancement appeared to be important predictors of ablation success. Patients who suffered recurrent AF showed enhancement in all portions of the LA, whereas patients who responded successfully to ablation showed enhancement limited primarily to the posterior wall and septum. Identifying the extent of LA fibrosis in patients with AF may become an important selection criterion for ablation procedures.

jâ•…G RO SS CARDIAC LANDMARKS AND ANATOMY Interventional therapy of AF has focused on the interruption of electrical conduction by isolating the pulmonary veins (PV) from the LA tissue. This is accomplished by applying radiofrequency energy around the PV ostia. Accurate definition of PV and LA anatomy is essential for planning catheter ablation procedures. Understanding the morphological characteristics of the LA in detail can achieve a more efficient and successful ablation and prevent potential complications. In the initial development of the PV isolation procedures, the size, number, and location of PVs were identified using invasive contrast venography. Although this can be done successfully, it greatly increases the procedure time, and provides only projection images of the PV. TEE can also identify PV anatomy and size; however, the sensitivity of this modality in identifying variations of PVs is dependent on operator experience [41]. Most centers now use CMR or MDCT to determine pulmonary vein anatomy

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C Electroanatomic Map

F igure 1 8 . 5 â•… Late gadolinium enÂ�Â�hanceÂ�ment magnetic resonance imaging (LGE-MRI) identifies areas of fibrosis within the left atrium in patients with atrial fibrillation. A, Segmented LGE-MRI reveals discrete areas of enhancement (brighter regions) in the posterior wall and septal area; B, Color 3D models improve dynamic range and better illuminate enhancement patterns; C, Electroanatomic map acquired during invasive electrophysiology (EP) study demonstrates discrete patterns of low voltage (within bounded white lines) detected in the left posterior wall and septum that correlate with the regions of LGE-MRI enhancement. These areas of low-voltage atrial tissue correspond histologically to areas of fibrosis. The extent of fibrosis appears to predict ablation success. Adapted from Ref. 40.

before catheter ablation procedures. Both techniques provide high-resolution 3D tomographic images of the PV and other mediastinal structures. These images can also be imported into 3D electrophysiological mapping systems that are an integral part of the procedure to combine anatomic and functional information during the procedure.

jâ•…A NATOMY OF THE PULMONARY VEINS Variation in PV anatomy is common. The majority of patients have 4 PVs, 2 superior and 2 inferior, with independent ostia draining separately into the LA (Figure 18.6) [42]. The right superior PV is close to the superior vena cava or right atrium, and the right inferior PV projects horizontally. The left superior PV is in close vicinity to the LAA, and the left inferior PV courses near the descending aorta and often the esophagus. Understanding the relationship

of the PVs to surrounding structures is essential for the appropriate and safe application of radiofrequency energy to those regions. A number of variations in the PVs have been described, the commonest of which are left common ostium (up to 83% of patients) and a separate origin for the right middle or accessory PV, which usually drains the right middle lobe or the superior segment of the right lower lung (up to 27% of patients) [41,43]. These variations occur due to inconsistent incorporation of the primitive common pulmonary vein into the body of the left atrium. Less incorporation leads to fusion of PV, whereas more incorporation leads to additional PV. Right-sided PV form first and have more developmental time to be incorporated into the left atrium. Therefore, it is more common to have additional veins on the right. Conversely, the left-sided PV form later and are more likely to have a common trunk [44]. Unusual pulmonary vein configurations can substantially influence the success rate of catheter ablation,

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steady-state cine CMR [50]. Although determination of the phases of the cardiac cycle can be performed with ECG-gated MDCT scanning and reconstruction, it is not always possible to perform if the patient is in AF at the time of the scan.

jâ•…P RO CEDURAL IMAGING Real-Time Cardiac Imaging

F igure 1 8 . 6 â•… Evaluation of pulmonary anatomy is important prior to ablation procedures. The multidetector computed tomography image depicts the typical anatomy of the left atrium–pulmonary vein (LA-PV) complex. The surface rendering shows a three-dimensional reconstruction seen from the posterior.

particularly if variant veins are not adequately treated. In addition, the variant pulmonary morphology can be the site of AF initiation. For example, a common ostium of the left-sided PVs results in a broad PV-atrial junction and has been shown to be an origin of arrhythmogenic ectopy [45]. Ectopic focus of AF initiation also has been demonstrated in the separate ostia of the right middle PV. In this case, AF can be cured by isolated catheter ablation of the arrhythmogenic PV [46]. Another important consideration before catheter ablation procedures is PV size. Knowledge of the diameter of the PV ostia is useful in the sizing of circular mapping catheters. It is also essential if balloon-based ablation catheters are to be used, as a close approximation of the balloon to the PV ostia is required for successful isolation. Baseline measurements of pulmonary vein diameter are also important to acquire before ablation procedures to compare with post procedure measurements. In rare cases, pulmonary vein stenosis can occur post ablation and occurs more commonly in ablation of smaller PV. The ostial geometries and size of PVs have been evaluated with MDCT and CMR. The PV ostia in patients with AF are ellipsoid with a longer superior–inferior dimension and funnel-shaped morphology [47]. Significant dilatation of both superior PVs is demonstrated among patients with paroxysmal AF and chronic AF [48]. After successful ablation of an arrhythmogenic PV, the dilated but nonablated PV has been shown to regress in size during longterm follow-up [49]. The ostial geometries also change with each phase of the cardiac cycle. The minimum diameter occurs in atrial systole and the maximum diameter in later atrial diastole. These phase differences account for a 33% difference in PV ostial diameters, assessed by

Although preprocedural imaging provides an anatomical roadmap for ablation procedures, real-time cardiac imaging is necessary to assess catheter location, elucidate cardiac anatomy, and improve the accuracy and safety of these procedures. Various imaging modalities are used in a typical ablation procedure. Traditionally, fluoroscopy has been employed to directly visualize catheter placement and manipulation. Upon gaining vascular access, each catheter is advanced to an intracardiac position under fluoroscopic guidance. However, fluoroscopy cannot provide detailed anatomical information of LA and PV anatomy and its surrounding structures. Intracardiac echocardiography (ICE) has proven to be a useful adjunctive imaging modality during ablation procedures [51]. Phased array ICE is a catheter with a linear array of piezoelectric crystals arranged longitudinally in order to produce a fan-shaped imaging plane that is parallel to the catheter tip. In typical clinical use, the ICE catheter is introduced via the femoral vein and advanced into the right atrial cavity. It can also be introduced via the internal jugular vein and advanced via the superior vena cava into the right atrium. More recently, a rotational ICE catheter has been described, similar to intravascular ultrasound, which uses a rotation of a single piezoelectric crystal [52]. Rotational ICE produces a 360-degree image around the catheter, allowing direct visualization of the LA endocardium and the adjacent structures such as the esophagus and aorta. Both phase array and rotational ICE provide real-time imaging. This allows intraprocedural imaging of the position of mapping and ablation catheters with respect to the anatomy of the LA, PV, and surrounding structures. It also allows for early detection of possible procedural complications.

jâ•…C AT HETERIZATION AF ablation procedures require access to the LA, which is achieved by transseptal puncture. Knowledge of septal anatomy and its relationship to adjacent structures is, therefore, essential to ensure safe and effective access to the LA. Transseptal puncture is relatively safe in experienced hands; however, potential life-threatening complications such as aortic or atrial perforation, cardiac tamponade, thrombotic formation, or air embolism can occur especially

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F igure 1 8 . 7 â•… Transseptal puncture is preformed with real-time imaging using intracardiac echocardiography (ICE). ICE images with the trans-

ducer placed in the high right atrium showing: (A) Tenting of the mid portion of the interatrial septum by the needle; (B) An example of a septum that is aneurismal. Adapted from Ref. 57.

in patients with variable atrial anatomy [53]. Therefore, the procedure is best performed with real-time cardiac imaging. Fluoroscopy provides sufficient information to allow safe transseptal puncture in the majority of cases. Under fluoroscopic visualization, a jump is seen when pulling a catheter down the septum, indicating the position of the foramen ovale [54]. The position is then confirmed by injection of contrast onto the septum. However, variations in septal anatomy, atrial or aortic root dilatation, the need for multiple punctures, and the desired ability to direct the catheter to specific locations often make fluoroscopy an inadequate tool for complex LA ablation procedures. Intraoperative TEE allows visualization of the interatrial septum and its relation to surrounding structures. It provides real-time evaluation of the procedure, with demonstration of tenting of the fossa before entry into the LA and visualization of the sheath advancing across the septum. It can also confirm access to the LA via injection of saline through the needle and visualization of bubbles in the LA. More recently, 3D TEE has been demonstrated as a useful tool in guiding transseptal puncture in patients undergoing AF ablation with the advantage of en face visualization of the fossa ovalis [55]. Using 3D TEE permits faster transatrial access with a single puncture attempt [55]. The disadvantage with using TEE is that the patient must be in a prone position, making airway management difficult and often requiring general anesthesia. ICE, which provides information similar to TEE, can be used in the conscious patient and is the modality of choice for accurate definition of the interatrial septum (Figure 18.7) [56]. jâ•…M ONITORING OF CATHETER POSITION ICE can be used to evaluate catheter movement during lesion delivery without the need for intermittent fluoroscopy. Although minor movements of the catheters are not

well appreciated fluoroscopically, these are accurately tracked and visualized by ICE. In fact, ICE has shown that significant catheter migration can occur during ablation, despite apparent catheter stability on fluoroscopy [58]. Proper positioning of ablation catheters is important as it helps to deliver lesions proximally, resulting in higher efficacy and lower risks of complications. ICE is also useful in monitoring the catheter–tissue interface during energy delivery [59]. Conventionally, temperature, power, and impedance are monitored during radiofrequency energy delivery. Observations with ICE have noted that impedance rise is preceded by a sudden dense shower of microbubbles thought to be due to tissue overheating. By titrating power output to limit microbubble formation, success rates have been improved with reduced risk of complications, including thromboembolic episodes [51]. jâ•…AVO IDING ESOPHAGEAL INJURY A rare but often fatal complication of AF ablation is an atrioesophageal fistula (Figure 18.8). Less serious esophageal injury (esophagitis, necrosis, or ulcer) as visualized by endoscopy has been reported in up to 35% of patients after ablation procedures [60]. Esophageal injury is believed to be due to thermal injury as a consequence of its close anatomic relationship to the posterior LA. For this reason, accurate identification of the course of the esophagus is an important tool to minimize the risk of thermal injury by either controlling or avoiding energy delivered in this region [61]. Several techniques have been used to locate the esophagus either before or during AF ablation, including MDCT [63], CMR [64], intraprocedural barium administration [65], and tagging techniques guided by electroanatomical mapping systems [63,64]. Reliance on remotely acquired images, however, does not ensure adequate intraprocedural localization of the esophagus especially due to a degree of esophageal motility [65]. Both phased array

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F igure 1 8 . 8 â•… Complications of catheter ablation procedures in an atrioesophageal fistula. (A) Cardiac multidetector computed tomography

image demonstrating an atrioesophageal fistula (F) from the left atrium (LA) to the esophagus marked by the gastric tube (Eso). Intracardiac echocardiography images (B and C) with the transducer placed in the high right atrium showing (B) early detection of pericardial effusion during the ablation procedure; C, Transseptal sheath in the LA with a mobile thrombus on its tip. Adapted from Refs. 62 and 57.

and rotational ICE offer the unique advantage of identifying the location of the esophagus throughout the entire procedure [52,66].

jâ•…E ARLY DETECTION OF COMPLICATIONS ICE imaging is a valuable tool for the early detection of complications during AF ablation procedure, consequently allowing for earlier intervention (Figure 18.8). Cardiac perforation and impending tamponade can occur and is usually detected along the inferior border of the RV and posterior LA. ICE allows for early intervention with pericardiocentesis and for continuous monitoring of reaccumulation during the drainage process. Thrombus can form on the transseptal sheath and ablation catheters and is identified using ICE. Although this finding may not affect specific acute intervention, the observation has led to a change in anticoagulation protocol during the procedure. Mild to moderate increase in PV flow velocity by ICE Doppler has been reported following PV ostial ablation procedure. Acute changes in PV flow immediately after ostial PV isolation do not appear to be a strong predictor of chronic PV stenosis [67].

jâ•…I MA GE INTEGRATION WITH ELECTROANATOMICAL MAPPING SYSTEMS To provide 3D orientation for catheter ablation, several electroanatomic mapping systems are commonly used to reconstruct a virtual 3D chamber anatomy. Each system

uses different technology (electromagnetic, ultrasound, and high-frequency radio waves) to generate a 3D image and localize the electrode catheter in space. These systems significantly lower fluoroscopy exposure, minimize risk to the patient, and improve patient outcomes. Electroanatomical mapping systems have been validated for anatomical and electrical accuracy in the atria as well as the ventricles. Anatomical structures such as PVs, LAA, and endocardial scars can be accurately identified and facilitate accurate creation of ablation lines. However, the resolution and accuracy of such virtual 3D chamber anatomy are limited by the number of acquired anatomical surface location points and the reliability of a true surface location of the catheter tip in areas with difficult catheter access. Integration of preacquired 3D images from MDCT or CMR with 3D electroanatomical mapping systems offers precise details of anatomy with real-time positioning of catheters during AF ablation (Figure 18.9). This has been shown to improve the success of ablation, decrease the occurrence of PV stenosis, and reduce fluoroscopic time [68,69]. Image integration occurs in 3 steps. The first is preprocedural acquisition by MDCT or CMR. The second process is segmentation of the acquired image into different regions to select the structures of interest. The final process is registration or alignment of the electroanatomical map and the CT or MR image. Registration of preacquired 3D images into the real-time mapping system can be achieved with 2 different approaches. Landmark registration is based on the alignment of 3 (or more) distinct anatomical structures on both the electroanatomical map and the CT or MR image. Surface registration involves alignment of the whole electroanatomic map and the CT or MR image. Although a reasonable accuracy can be achieved with image integration, preprocedural anatomic images carry

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F igure 1 8 . 9 â•…Integration of preacquired images from multidetector computed tomography with electroanatomical mapping systems provides 3D orientation for catheter navigation during ablation procedures. Shown are 64-slice CT images of the LA merged with an electroanatomical map created with a roving catheter and an advanced mapping system. The left image represents an internal view of the LA, left-sided PVs, and appendage. Radiofrequency lesions are marked along the vein ostium. The right image is an anterior–posterior view. In this case, image integration allowed a more defined ablation procedure along the scar or low-voltage borders in this LA. Both images are mathematically merged during the procedure. LSPV indicates left superior PV; LIPV, left inferior PV; RSPV, right superior PV; LAA, left atrial appendage. Adapted from Ref. 70.

inherent disadvantages. LA anatomy is variable and depends on many factors, including cardiac rhythm, volume status, respiration [71], and deformation of the left atrium by electrophysiological catheters during the procedure [72]. The image integration process is, therefore, affected by changes in atrial volumes and anatomy between the imaging session and AF ablation session. These differences have been shown to be considerable in patients with larger atria [72]. In patients with AF, significant changes in LA volume occur over the cardiac cycle and may represent a potential source of error during image registration [73]. Similarly, changes in heart rate and rhythm between the preprocedure image and generation of electroanatomic map may result in errors of image registration [74]. Image fusion and nonfluoroscopic catheter visualization can therefore probably not fully replace fluoroscopy or other forms of direct catheter visualization during catheter ablation procedures, such as ICE. There are ongoing efforts to perform ablations under the guidance of CMR and cardiac CT. Using CMR for realtime imaging has several advantages, mainly elimination of patient and staff radiation exposure as well as improvement in real-time soft tissue resolution for procedural guidance. However, previous concerns including catheter heating, current induction, image distortion, and electromagnetic interference have limited real-time CMR use. A recent study, however, reported the feasibility and safety of real-time MRI-guided cardiac interventions in both animals and humans [75]. This study demonstrated accurate anatomic catheter positioning and successful recording of intracardiac electrograms as well as programmed stimulation. In addition, no significant tissue damage was noted in the animal autopsy after ablation, suggesting that catheter heating may be safely avoided in such procedures [75].

jâ•…P OS TPROCEDURAL IMAGING Predicting Success of Procedure Recurrence of AF after successful catheter ablation is not uncommon, and the predictors of recurrence are not completely understood. Restoration of sinus rhythm by catheter ablation has been shown to improve cardiac function presumably by cardiac remodeling. LV systolic and diastolic function improves dramatically if sinus rhythm is maintained [76–78]. This finding is particularly striking in patients with congestive heart failure [76]. Changes in LA function, however, have been variably described. A reduction in LA size can often be documented after catheter ablation regardless of the success of the procedure. This finding likely results from both atrial remodeling and scar formation. LA volumes measured either before or after catheter ablation have also been shown to correlate with the success of the procedure. The mean LA volume before ablation appears to be significantly larger in patients with AF recurrence [79]. In one study, patients with pre-ablation LA volumes .135 mL (during ventricular mid-diastole) on contrast-enhanced MDCT were most likely to experience recurrent AF [79]. Using TTE, an indexed LA volume of .34 mL/m2 after ablation has also been shown to predict AF recurrence [80]. These findings suggest that patients with a dilated left atrium are unlikely to maintain sinus rhythm after catheter ablation procedures. Acutely, restoration of sinus rhythm by catheter ablation is followed by transient atrial stunning as well as a transient decrease in the LAA emptying velocity by TE [81]. For this reason, anticoagulation is started

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Assessment of Complications

Pulmonary Vein Stenosis

F igure 1 8 . 1 0 â•… Radiofrequency ablation results in scarring around the pulmonary vein and of the left atrial wall. An axial late gadolinium enhancement magnetic resonance imaging image of the left atrium is shown. The scarred myocardium around the pulmonary veins is enhanced (appears bright) and represents areas of previous ablations. Arrhythmia recurrence is often a result of incomplete ablation. Adapted from Ref. 83.

immediately after these procedures. However, whether the LA function improves after this period is a matter of debate. Studies have investigated the impact of extensive AF ablation on atrial function with conflicting results largely because of variations in measurement of LA function and in method of catheter ablations. Some studies have suggested improvement of LA function [81], whereas others suggest worsening of LA function [82,83]. The role of postprocedure atrial dysfunction as a predictor of AF recurrence is a topic of ongoing research. Radiofrequency ablation results in scarring around the pulmonary vein and of the LA wall. This scar can be observed as an accumulation of gadolinium contrast on LGE-MRI (Figure 18.10). Clinically, arrhythmia recurrence is often a result of incomplete ablation or electrical reconnection [84]. LGE-MRI therefore has the potential to noninvasively assess the completeness of ablation by providing an anatomic map of the ablation lines [85]. Studies have shown that the extent of scar correlates with patient outcome after catheter ablation. AF recurrence during the first year has been associated with a lesser degree of PV and LA scarring [86]. This finding is especially significant for the right inferior pulmonary vein, which is often technically difficult to completely isolate. LGE-MRI could serve as a useful tool either after the procedure to assess patient outcomes or as a future real-time tool to guide ablation during interventional CMR.

PV stenosis is a complication of catheter ablation of AF, resulting from fibrosis and contraction of scar within the PV musculature after application of radiofrequency energy [87–89]. The use of ICE to identify PV ostia and to avoid ablation within the PV itself has significantly reduced the incidence of this complication. Patients typically present with dyspnea, cough, hemoptysis, and recurrent lung infections; however, many patients are asymptomatic even in the setting of severe stenosis or occlusion. Therefore, some have advocated routine screening for PV stenosis after ablation. PV stenosis severity is defined according to the percentage reduction in luminal diameter: mild (,50%), moderate (50%–70%), or severe (.70%) in recent consensus guidelines [2]. The PV diameter changes within the cardiac cycle and therefore should be measured at its maximal excursion occurring in atrial diastole. However, even with this approach, measurements of PV diameter are often not precise. Therefore, assessment of PV stenosis is best achieved by comparing preprocedure with postprocedure images (Figure 18.11). MDCT and CMR are considered the gold standard noninvasive imaging tests to identify PV stenosis. Although pulmonary angiography is accurate, due to its invasive nature, this is not the preferred option. Functional testing with single photon emission computed tomography and MR perfusion scanning can detect decreased perfusion in patients with PV stenosis, which later improves following restoration of flow [78,88]. TEE can identify PV stenosis although its sensitivity is dependent on user experience. TEE has also been shown to underestimate PV ostial diameters [41]. The functional significance of a stenosis can be confirmed with color and pulsedwave Doppler assessment of PV flow on TEE (Figure 18.11). Turbulence and aliasing of the color Doppler and increased pulsed-wave Doppler velocities are required to confirm the presence of hemodynamically significant stenosis. There is no consensus as to the exact velocity that defines stenosis. Early case reports quoted velocities in excess of 160 cm/s; however, velocities anywhere between 80 and 110 cm/s have also been reported [92].

Esophageal Injury LA–esophageal fistula is a very rare complication of ablation procedures, but it is fatal in most reported cases [62]. Fistula formation is the result of thermal injury of esophageal tissues from application of radiofrequency energy to the posterior LA immediately adjacent to the esophagus. Symptoms related to LA–esophageal fistula typically emerge 1 to 5 weeks after treatment. Fever, gastrointestinal bleed, malaise, dysphasia, and neurological symptoms in patients with recent catheter ablation of AF should raise

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arrhythmias, especially AF. The initial evaluation uses imaging to determine the presence of structural heart disease, assess thromboembolic risk, as well as guide therapy. Real-time imaging and image integration are essential for accuracy and safety of catheter ablation procedures. Finally, imaging during follow-up of patients assesses complications as well as predicts success of treatment.

jâ•…R EF ERENCES

F igure 1 8 . 1 1 â•… Pulmonary vein (PV) stenosis is a complication of

catheter ablation procedures. Assessment of PV stenosis is best achieved by comparison of preprocedure with postprocedure images. Shown are multidetector computed tomography reformatted images of the left atrium and pulmonary veins for a patient before (A) and after (B) catheter ablation. The preprocedure images of left superior pulmonary vein (LSPV) and left inferior pulmonary vein (LIPV) show no ostial stenosis (black arrow). The postprocedure images reveal ostial stenosis of both the LSPV and LIPV. Transesophageal echocardiography can determine the functional significance of a pulmonary vein stenosis. C, Significant ostial narrowing with turbulence and aliasing of the color Doppler on transesophageal echocardiography; and (D) Pulsed-wave Doppler of pulmonary venous inflow .100 cm/s confirms hemodynamically significant stenosis. Parts c and d are representative images from another patient. Adapted from Refs. 90 and 91.

suspicion for fistula formation. Endoscopy and TEE should not be performed because of the risk of further esophageal injury and air emboli. The examination of choice is CT with water-soluble contrast, which allows the fistula to be visualized. Magnetic resonance imaging can also be used in this situation. Immediate surgical repair is indicated because spontaneous resolution of a LA–esophageal fistula has not been reported.

jâ•…C ONCLUSION In summary, multimodality imaging is critical in the evaluation, treatment, and follow-up of patients with atrial

â•‡ 1. Fuster V, Ryden LE, Cannom DS, et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation. Europace. 2006;8(9):651–745. â•‡ 2. Calkins H, Brugada J, Packer DL, et al. HRS/EHRA/ECAS expert consensus statement on catheter and surgical ablation of atrial fibrillation: recommendations for personnel, policy, procedures and follow-up. Europace. 2007;9(6):335–379. â•‡ 3. Vaziri SM, Larson MG, Benjamin EJ, Levy D. Echocardiographic predictors of nonrheumatic atrial fibrillation. The Framingham Heart Study. Circulation. 1994;89(2):724–730. â•‡ 4. Okura H, Takada Y, Kubo T, et al. Tissue Doppler-derived index of left ventricular filling pressure, E/E’, predicts survival of patients with non-valvular atrial fibrillation. Heart. 2006;92(9):1248–1252. â•‡ 5. Nagueh SF, Kopelen HA, Quinones MA. Assessment of left ventricular filling pressures by Doppler in the presence of atrial fibrillation. Circulation. 1996;94(9):2138–2145. â•‡ 6. Klein AL, Murray RD, Grimm RA. Role of transesophageal echocardiography-guided cardioversion of patients with atrial fibrillation. J Am Coll Cardiol. 2001;37(3):691–704. â•‡ 7. Echocardiographic predictors of stroke in patients with atrial fibrillation: a prospective study of 1066 patients from 3 clinical trials. Arch Intern Med. 1998;158(12):1316–1320. â•‡ 8. Transesophageal echocardiographic correlates of thromboembolism in high-risk patients with nonvalvular atrial fibrillation. The Stroke Prevention in Atrial Fibrillation Investigators Committee on Echocardiography. Ann Intern Med. 1998;128(8):639–647. â•‡ 9. Zabalgoitia M, Halperin JL, Pearce LA, Blackshear JL, Asinger RW, Hart RG. Transesophageal echocardiographic correlates of clinical risk of thromboembolism in nonvalvular atrial fibrillation. Stroke Prevention in Atrial Fibrillation III Investigators. J Am Coll Cardiol. 1998;31(7):1622–1626. 10. Bernhardt P, Schmidt H, Hammerstingl C, Luderitz B, Omran H. Patients at high risk with atrial fibrillation: a prospective and serial follow-up during 12 months with transesophageal echocardiography and cerebral magnetic resonance imaging. J Am Soc Echocardiogr. 2005;18(9):919–924. 11. Subramaniam B, Riley MF, Panzica PJ, Manning WJ. Transesophageal echocardiographic assessment of right atrial appendage anatomy and function: comparison with the left atrial appendage and implications for local thrombus formation. J Am Soc Echocardiogr. 2006;19(4):429–433. 12. Omran H, Jung W, Rabahieh R, et al. Imaging of thrombi and assessment of left atrial appendage function: a prospective study comparing transthoracic and transoesophageal echocardiography. Heart. 1999;81:192–198. 13. Fatkin D, Scalia G, Jacobs N, et al. Accuracy of biplane transesophageal echocardiography in detecting left atrial thrombus. Am J Cardiol. 1996;77(4):321–323. 14. Gottlieb I, Pinheiro A, Brinker JA, et al. Diagnostic accuracy of arterial phase 64-slice multidetector CT angiography for left atrial appendage thrombus in patients undergoing atrial fibrillation ablation. J Cardiovasc Electrophysiol. 2008;19(3):247–251. 15. Kim YY, Klein AL, Halliburton SS, et al. Left atrial appendage filling defects identified by multidetector computed tomography in patients undergoing radiofrequency pulmonary vein antral isolation:

296

a comparison with transesophageal echocardiography. Am Heart J. 2007;154(6):1199–1205. 16. Leung DY, Davidson PM, Cranney GB, Walsh WF. Thromboembolic risks of left atrial thrombus detected by transesophageal echocardiogram. Am J Cardiol. 1997;79(5):626–629. 17. Bernhardt P, Schmidt H, Hammerstingl C, Luderitz B, Omran H. Patients with atrial fibrillation and dense spontaneous echo contrast at high risk a prospective and serial follow-up over 12 months with transesophageal echocardiography and cerebral magnetic resonance imaging. J Am Coll Cardiol. 2005;45(11):1807–1812. 18. Ren JF, Marchlinski FE, Callans DJ. Left atrial thrombus associated with ablation for atrial fibrillation: identification with intracardiac echocardiography. J Am Coll Cardiol. 2004;43(10):1861–1867. 19. Goldman ME, Pearce LA, Hart RG, et al. Pathophysiologic correlates of thromboembolism in nonvalvular atrial fibrillation: I. Reduced flow velocity in the left atrial appendage (The Stroke Prevention in Atrial Fibrillation [SPAF-III] study). J Am Soc Echocardiogr. 1999;12(12):1080–1087. 20. Mugge A, Kuhn H, Nikutta P, Grote J, Lopez JA, Daniel WG. Assessment of left atrial appendage function by biplane transesophageal echocardiography in patients with nonrheumatic atrial fibrillation: identification of a subgroup of patients at increased embolic risk. J Am Coll Cardiol. 1994;23(3):599–607. 21. Fatkin D, Kelly RP, Feneley MP. Relations between left atrial appendage blood flow velocity, spontaneous echocardiographic contrast and thromboembolic risk in vivo. J Am Coll Cardiol. 1994;23(4):961–969. 22. Siostrzonek P, Koppensteiner R, Gossinger H, et al. Hemodynamic and hemorheologic determinants of left atrial spontaneous echo Â�contrast and thrombus formation in patients with idiopathic dilated cardiomyopathy. Am Heart J. 1993;125(2 Pt 1):430–434. 23. Dittrich HC, Pearce LA, Asinger RW, et al; for the Stroke Prevention in Atrial Fibrillation Investigators. Left atrial diameter in nonvalvular atrial fibrillation: an echocardiographic study. Am Heart J. 1999;137(3):494–499. 24. Manning WJ, Leeman DE, Gotch PJ, Come PC. Pulsed Doppler evaluation of atrial mechanical function after electrical cardioversion of atrial fibrillation. J Am Coll Cardiol. 1989;13(3):617–623. 25. Dittrich HC, Erickson JS, Schneiderman T, Blacky AR, Savides T, Nicod PH. Echocardiographic and clinical predictors for outcome of elective cardioversion of atrial fibrillation. Am J Cardiol. 1989;63(3):193–197. 26. Brodsky MA, Allen BJ, Capparelli EV, Luckett CR, Morton R, Henry WL. Factors determining maintenance of sinus rhythm after chronic atrial fibrillation with left atrial dilatation. Am J Cardiol. 1989;63(15):1065–1068. 27. Themistoclakis S, Schweikert RA, Saliba WI, et al. Clinical predictors and relationship between early and late atrial tachyarrhythmias after pulmonary vein antrum isolation. Heart Rhythm. 2008;5(5):679–685. 28. Lester SJ, Ryan EW, Schiller NB, Foster E. Best method in clinical practice and in research studies to determine left atrial size. Am J Cardiol. 1999;84(7):829–832. 29. Kircher B, Abbott JA, Pau S, et al. Left atrial volume determination by biplane two-dimensional echocardiography: validation by cine computed tomography. Am Heart J. 1991;121(3 Pt 1):864–871. 30. Rodevan O, Bjornerheim R, Ljosland M, Maehle J, Smith HJ, Ihlen H. Left atrial volumes assessed by three- and two-dimensional echocardiography compared to MRI estimates. Int J Card Imaging. 1999;15(5):397–410. 31. Jarvinen VM, Kupari MM, Hekali PE, Poutanen VP. Right atrial MR imaging studies of cadaveric atrial casts and comparison with right and left atrial volumes and function in healthy subjects. Radiology. 1994;191(1):137–142. 32. Anwar AM, Soliman OI, Geleijnse ML, Nemes A, Vletter WB, ten Cate FJ. Assessment of left atrial volume and function by real-time threedimensional echocardiography. Int J Cardiol. 2008;123(2):155–161. 33. Di Salvo G, Caso P, Lo Piccolo R, et al. Atrial myocardial deformation properties predict maintenance of sinus rhythm after external

Multimodality Imaging in Cardiovascular Medicine

cardioversion of recent-onset lone atrial fibrillation: a color Doppler myocardial imaging and transthoracic and transesophageal echocardiographic study. Circulation. 2005;112(3):387–395. 34. Schneider C, Malisius R, Krause K, et al. Strain rate imaging for functional quantification of the left atrium: atrial deformation predicts the maintenance of sinus rhythm after catheter ablation of atrial fibrillation. Eur Heart J. 2008;29(11):1397–1409. 35. Wang T, Wang M, Fung JW, et al. Atrial strain rate echocardiography can predict success or failure of cardioversion for atrial fibrillation: a combined transthoracic tissue Doppler and transoesophageal imaging study. Int J Cardiol. 2007;114(2):202–209. 36. Thomas L, McKay T, Byth K, Marwick TH. Abnormalities of left atrial function after cardioversion: an atrial strain rate study. Heart. 2007;93(1):89–95. 37. Antonielli E, Pizzuti A, Palinkas A, et al. Clinical value of left atrial appendage flow for prediction of long-term sinus rhythm maintenance in patients with nonvalvular atrial fibrillation. J Am Coll Cardiol. 2002;39(9):1443–1449. 38. Morillo CA, Klein GJ, Jones DL, Guiraudon CM. Chronic rapid atrial pacing. Structural, functional, and electrophysiological characteristics of a new model of sustained atrial fibrillation. Circulation. 1995;91(5):1588–1595. 39. Boldt A, Wetzel U, Lauschke J, et al. Fibrosis in left atrial tissue of patients with atrial fibrillation with and without underlying mitral valve disease. Heart. 2004;90(4):400–405. 40. Oakes RS, Badger TJ, Kholmovski EG, et al. Detection and Â�quantification of left atrial structural remodeling with delayedenhancement magnetic resonance imaging in patients with atrial fibrillation. Circulation. 2009. 41. Wood MA, Wittkamp M, Henry D, et al. A comparison of pulmonary vein ostial anatomy by computerized tomography, echocardiography, and venography in patients with atrial fibrillation having radiofrequency catheter ablation. Am J Cardiol. 2004;93(1):49–53. 42. Marom EM, Herndon JE, Kim YH, McAdams HP. Variations in pulmonary venous drainage to the left atrium: implications for radiofrequency ablation. Radiology. 2004;230(3):824–829. 43. Benini K, Marini M, Del Greco M, Nollo G, Manera V, Centonze M. Role of multidetector computed tomography in the anatomical definition of the left atrium-pulmonary vein complex in patients with atrial fibrillation. Personal experience and pictorial assay. Radiol Med. 2008;113(6):779–798. 44. Kato R, Lickfett L, Meininger G, et al. Pulmonary vein anatomy in patients undergoing catheter ablation of atrial fibrillation: lessons learned by use of magnetic resonance imaging. Circulation. 2003;107(15):2004–2010. 45. Schwartzman D, Bazaz R, Nosbisch J. Common left pulmonary vein: a consistent source of arrhythmogenic atrial ectopy. J Cardiovasc Electrophysiol. 2004;15(5):560–566. 46. Tsao HM, Wu MH, Yu WC, et al. Role of right middle pulmonary vein in patients with paroxysmal atrial fibrillation. J Cardiovasc Electrophysiol. 2001;12(12):1353–1357. 47. Wittkampf FH, Vonken EJ, Derksen R, et al. Pulmonary vein ostium geometry: analysis by magnetic resonance angiography. Circulation. 2003;107(1):21–23. 48. Tsao HM, Yu WC, Cheng HC, et al. Pulmonary vein dilation in patients with atrial fibrillation: detection by magnetic resonance imaging. J Cardiovasc Electrophysiol. 2001;12(7):809–813. 49. Tsao HM, Wu MH, Huang BH, et al. Morphologic remodeling of pulmonary veins and left atrium after catheter ablation of atrial fibrillation: insight from long-term follow-up of three-dimensional magnetic resonance imaging. J Cardiovasc Electrophysiol. 2005;16(1): 7–12. 50. Lickfett L, Dickfeld T, Kato R, et al. Changes of pulmonary vein orifice size and location throughout the cardiac cycle: dynamic analysis using magnetic resonance cine imaging. J Cardiovasc Electrophysiol. 2005;16(6):582–588. 51. Marrouche NF, Martin DO, Wazni O, et al. Phased-array intracardiac echocardiography monitoring during pulmonary vein isolation in patients with atrial fibrillation: impact on outcome and complications. Circulation. 2003;107(21):2710–2716.

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52. Helms A, West JJ, Patel A, et al. Real-time rotational ICE imaging of the relationship of the ablation catheter tip and the esophagus during atrial fibrillation ablation. J Cardiovasc Electrophysiol. 2009;20(2):130–137. 53. De Ponti R, Zardini M, Storti C, Longobardi M, Salerno-Uriarte JA. Trans-septal catheterization for radiofrequency catheter ablation of cardiac arrhythmias. Results and safety of a simplified method. Eur Heart J. 1998;19(6):943–950. 54. Brockenbrough EC, Braunwald E, Ross J Jr. Transseptal left heart catheterization. A review of 450 studies and description of an improved technic. Circulation. 1962;25:15–21. 55. Chierchia GB, Capulzini L, de Asmundis C, et al. First experience with real-time three-dimensional transoesophageal echocardiographyguided transseptal in patients undergoing atrial fibrillation ablation. Europace. 2008;10(11):1325–1328. 56. Daoud EG, Kalbfleisch SJ, Hummel JD. Intracardiac echocardiography to guide transseptal left heart catheterization for radiofrequency catheter ablation. J Cardiovasc Electrophysiol. 1999;10(3):358–363. 57. Saliba W, Thomas J. Intracardiac echocardiography during catheter ablation of atrial fibrillation. Europace. 2008;10(suppl 3):iii42–iii47. 58. Chu E, Kalman JM, Kwasman MA, et al. Intracardiac echocardiography during radiofrequency catheter ablation of cardiac arrhythmias in humans. J Am Coll Cardiol. 1994;24(5):1351–1357. 59. Kalman JM, Fitzpatrick AP, Olgin JE, et al. Biophysical characteristics of radiofrequency lesion formation in vivo: dynamics of catheter tip-tissue contact evaluated by intracardiac echocardiography. Am Heart J. 1997;133(1):8–18. 60. Marrouche NF, Guenther J, Segerson NM, et al. Randomized comparison between open irrigation technology and intracardiac-echo-guided energy delivery for pulmonary vein antrum isolation: procedural parameters, outcomes, and the effect on esophageal injury. J Cardiovasc Electrophysiol. 2007;18(6):583–588. 61. Cummings JE, Schweikert RA, Saliba WI, et al. Assessment of temperature, proximity, and course of the esophagus during radiofrequency ablation within the left atrium. Circulation. 2005; 112(4):459–464. 62. Schley P, Gulker H, Horlitz M. Atrio-oesophageal fistula following circumferential pulmonary vein ablation: verification of diagnosis with multislice computed tomography. Europace. 2006;8(3):189–190. 63. Piorkowski C, Hindricks G, Schreiber D, et al. Electroanatomic reconstruction of the left atrium, pulmonary veins, and esophagus compared with the “true anatomy” on multislice computed tomography in patients undergoing catheter ablation of atrial fibrillation. Heart Rhythm. 2006;3(3):317–327. 64. Cummings JE, Schweikert RA, Saliba WI, et al. Brief communication: atrial-esophageal fistulas after radiofrequency ablation. Ann Intern Med. 2006;144(8):572–574. 65. Good E, Oral H, Lemola K, et al. Movement of the esophagus during left atrial catheter ablation for atrial fibrillation. J Am Coll Cardiol. 2005;46(11):2107–2110. 66. Ren JF, Lin D, Marchlinski FE, Callans DJ, Patel V. Esophageal imaging and strategies for avoiding injury during left atrial ablation for atrial fibrillation. Heart Rhythm. 2006;3(10):1156–1161. 67. Saad EB, Cole CR, Marrouche NF, et al. Use of intracardiac echocardiography for prediction of chronic pulmonary vein stenosis after ablation of atrial fibrillation. J Cardiovasc Electrophysiol. 2002;13(10):986–989. 68. Martinek M, Nesser HJ, Aichinger J, Boehm G, Purerfellner H. Impact of integration of multislice computed tomography imaging into three-dimensional electroanatomic mapping on clinical outcomes, safety, and efficacy using radiofrequency ablation for atrial fibrillation. Pacing Clin Electrophysiol. 2007;30(10): 1215–1223. 69. Kistler PM, Rajappan K, Jahngir M, et al. The impact of CT image integration into an electroanatomic mapping system on clinical outcomes of catheter ablation of atrial fibrillation. J Cardiovasc Electrophysiol. 2006;17(10):1093–1101.

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70. Burke MC, Roberts MJ, Knight BP. Integration of cardiac imaging and electrophysiology during catheter ablation procedures for atrial fibrillation. J Electrocardiol. 2006;39(4 suppl):S188–S192. 71. Noseworthy PA, Malchano ZJ, Ahmed J, Holmvang G, Ruskin JN, Reddy VY. The impact of respiration on left atrial and pulmonary venous anatomy: implications for image-guided intervention. Heart Rhythm. 2005;2(11):1173–1178. 72. Heist EK, Chevalier J, Holmvang G, et al. Factors affecting error in integration of electroanatomic mapping with CT and MR imaging during catheter ablation of atrial fibrillation. J Interv Card Electrophysiol. 2006;17(1):21–27. 73. Patel AR, Fatemi O, Norton PT, et al. Cardiac cycle-dependent left atrial dynamics: implications for catheter ablation of atrial fibrillation. Heart Rhythm. 2008;5(6):787–793. 74. Patel AM, Heist EK, Chevalier J, et al. Effect of presenting rhythm on image integration to direct catheter ablation of atrial fibrillation. J Interv Card Electrophysiol. 2008;22(3):205–210. 75. Nazarian S, Kolandaivelu A, Zviman MM, et al. Feasibility of realtime magnetic resonance imaging for catheter guidance in electrophysiology studies. Circulation. 2008;118(3):223–229. 76. Reant P, Lafitte S, Jais P, et al. Reverse remodeling of the left cardiac chambers after catheter ablation after 1 year in a series of patients with isolated atrial fibrillation. Circulation. 2005;112(19): 2896–2903. 77. Takahashi Y, O’Neill MD, Hocini M, et al. Effects of stepwise ablation of chronic atrial fibrillation on atrial electrical and mechanical properties. J Am Coll Cardiol. 2007;49(12):1306–1314. 78. Hsu LF, Jais P, Sanders P, et al. Catheter ablation for atrial fibrillation in congestive heart failure. N Engl J Med. 2004;351(23): 2373–2783. 79. Helms AS, West JJ, Patel A, et al. Relation of left atrial volume from three-dimensional computed tomography to atrial fibrillation recurrence following ablation. Am J Cardiol. 2009; 103(7):989–993. 80. Shin SH, Park MY, Oh WJ, et al. Left atrial volume is a predictor of atrial fibrillation recurrence after catheter ablation. J Am Soc Echocardiogr. 2008;21(6):697–702. 81. Welch PJ, Afridi I, Joglar JA, et al. Effect of radiofrequency ablation on atrial mechanical function in patients with atrial flutter. Am J Cardiol. 1999;84(4):420–425. 82. Lemola K, Desjardins B, Sneider M, et al. Effect of left atrial circumferential ablation for atrial fibrillation on left atrial transport function. Heart Rhythm. 2005;2(9):923–928. 83. Wylie JV Jr, Peters DC, Essebag V, Manning WJ, Josephson ME, Hauser TH. Left atrial function and scar after catheter ablation of atrial fibrillation. Heart Rhythm. 2008;5(5):656–662. 84. Verma A, Kilicaslan F, Pisano E, et al. Response of atrial fibrillation to pulmonary vein antrum isolation is directly related to resumption and delay of pulmonary vein conduction. Circulation. 2005;112(5):627–635. 85. Peters DC, Wylie JV, Hauser TH, et al. Detection of pulmonary vein and left atrial scar after catheter ablation with three-dimensional navigator-gated delayed enhancement MR imaging: initial experience. Radiology. 2007;243(3):690–695. 86. Peters DC, Wylie JV, Hauser TH, et al. Recurrence of atrial fibrillation correlates with the extent of post-procedural late gadolinium enhancement. JACC: Cardiovascular Imaging. 2009;2(3):9. 87. Packer DL, Keelan P, Munger TM, et al. Clinical presentation, investigation, and management of pulmonary vein stenosis complicating ablation for atrial fibrillation. Circulation. 2005;111(5):546–554. 88. Saad EB, Rossillo A, Saad CP, et al. Pulmonary vein stenosis after radiofrequency ablation of atrial fibrillation: functional characterization, evolution, and influence of the ablation strategy. Circulation. 2003;108(25):3102–3107. 89. Cappato R, Calkins H, Chen SA, et al. Worldwide survey on the methods, efficacy, and safety of catheter ablation for human atrial fibrillation. Circulation. 2005;111(9):1100–1105.

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90. Niinuma H, George RT, Arbab-Zadeh A, Lima JA, Henrikson CA. Imaging of pulmonary veins during catheter ablation for atrial fibrillation: the role of multi-slice computed tomography. Europace. 2008;10(suppl 3):iii14–iii21. 91. Gabriel RS, Klein AL. Managing catheter ablation for atrial fibrillation: the role of echocardiography. Europace. 2008;10(suppl 3): iii8–iii13. 92. Sigurdsson G, Troughton RW, Xu XF, et al. Detection of pulmonary vein stenosis by transesophageal echocardiography: comparison with multidetector computed tomography. Am Heart J. 2007;153(5):800–806. 93. Lang RM, Bierig M, Devereux RB, et al. Recommendations for chamber quantification: a report from the American Society of

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Echocardiography’s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr. 2005;18(12):1440–1463. 94. Jongbloed MR, Dirksen MS, Bax JJ, et al. Atrial fibrillation: multi-detector row CT of pulmonary vein anatomy prior to radiofrequency catheter ablation—initial experience. Radiology. 2005;234(3):702–709. 95.â•‡ Reddy VY, Schmidt EJ, Holmvang G, Fung M. Arrhythmia recurrence after atrial fibrillation ablation: can magnetic resonance imaging identify gaps in atrial ablation lines? J Cardiovasc Electrophysiol. 2008;19(4):434–437.

19

Noninvasive Atherosclerosis ImagingÂ€ for Risk Stratification

aL Len j. TaYL or

jâ•… RAT IONALE FOR SCREENING

PatriCK j. Devine

The first clinical manifestation of CHD can range from stable angina to unstable angina, acute myocardial infarction, and even sudden cardiac death [4]. Screening for the early detection of preclinical atherosclerosis is based on the presumption that subjects at increased risk of an adverse cardiac event can be identified and offered appropriate preventive therapy and education for behavioral change. Thus, the risk stratification of asymptomatic patients and identification of high-risk patients are critical initial steps in preventing future adverse cardiac events such as myocardial infarction and sudden cardiac death.

Although mortality from coronary heart disease (CHD) has declined significantly over the past 3 decades, it remains the leading cause of death in adults. It is estimated that the lifetime risk of CHD in asymptomatic patients at age 40 years is 49% in men and 32% in women [1]. In light of this, there is considerable interest in identifying heightened risk for CHD at an early, presymptomatic stage so that appropriate preventive therapy can be offered. The concepts of risk assessment and reduction remain the cornerstones of preventive cardiology practice. To achieve this, cardiovascular risk scoring tools, such as the Framingham Risk Score (FRS), are proposed to guide the selection and calibrate the intensity with which Â�preventive cardiology is delivered [2,3]. The FRS has moderate Â�accuracy for the prediction of incident CHD over Â�modest time periods and is practical due to its inclusion of modifiable risk factors. However, limitations include lack of inclusion of all contributory factors for CHD (eg, Â�lifestyle factors and family history), reduced Â�applicability in Â�non-Caucasian ethnic populations and select age groups (particularly the old and the young), assignment of a large group of middle-aged patients with intermediate CHD risk whose treatments and targets are less informed by guidelines, and Â�inaccurate discrimination of lifelong risk for CHD. Subsequently, many patients are not fully identified as Â�candidates for preventive therapy with medications such as statins and aspirin because they are deemed low or Â�intermediate risk for incident CHD. Presymptomatic testing through Â�detection of subclinical atherosclerosis provides a tool for the refinement of Â�cardiovascular risk assessment, most appropriately those subjects classified as intermediate risk by the FRS. Through the assessment of subclinical Â�atherosclerosis either anatomically with carotid ultrasound, coronary computed tomography, Â�magnetic Â�resonance imaging, or functionally with brachial Â�flow-mediated Â�dilation, a patient’s individual Â�cardiovascular risk can be better defined.

jâ•…T HE FRAMINGHAM RISK SCORE: APPLICATION, LIMITATIONS The FRS is a well-characterized risk assessment tool recommended as a first step in coronary risk assessment. By including risk factors of gender, age, total cholesterol, High Density Lipoprotein (HDL) cholesterol, systolic blood pressure, and cigarette use, a patient’s 10-year risk for myocardial infarction and cardiac death can be easily estimated. The clinical importance of the FRS is underscored by its inclusion in guidelinebased publications such as the The National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III guidelines released in 2001 [5]. These guidelines continue to support the panel’s previous recommendations for intensive management of Low Density Lipoprotein (LDL) cholesterol in individuals known to have CHD or CHD risk equivalents, while providing a new focus of intensive management of LDL for primary prevention in individuals with multiple risk factors. Individuals with 2 or more risk factors are recommended to have their FRS calculated. Individuals with a 10-year predicted CHD risk of 20% or higher (high risk) are considered to have CHD risk equivalents and urged to maintain an LDL level of ,100 mg/dL. For those with an FRS of 10% to 20% (intermediate risk), an LDL goal of ,130 mg/dL is advised. Low-risk patients have an FRS of ,10% (Figure 19.1). The NCEP ATP III guidelines were recently applied to 13â•›769 participants in the Third National Health and Nutrition 299

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300

Identify number of cardiac risk factors and calculate FRS

0–1 risk factor

Lipid lowering therapy if LDL 190 mg/dl F ig ure 1 9 . 1 â•… Using FRS in the identification of asymptomatic patients for lipid lowering therapy. FRS, Framingham Risk Score; CHD, coronary heart disease.

2 or more risk factors

FRS 0–10%

Lipid lowering therapy if LDL 160 mg/dl

Examination Survey [6]. Extrapolating these results to the US population between the ages of 20 to 79 years revealed that approximately 81.7% (140 million adults) fell into the low-risk group, 15.5% (23 million adults) fell into the intermediaterisk group, whereas only 2.9% (4 million adults) fell into the high 10-year risk of CHD. Thus, only 2.9% of the population would be defined as having CHD equivalents and, therefore, be recommended for intensive lipid therapy according to the new NCEP ATP III guidelines. Clearly, this represents a gross underestimation of overall lifetime cardiovascular risk by the FRS and underestimates the size of the intermediate-risk group among middle-aged individuals. Whereas the Framingham Heart Study has been a rich source of information regarding risk assessment for Â�cardiovascular diseases, several limitations need to be Â�considered when applying the FRS to an individual patient. Young patients were underrepresented and had few coronary events in the FHS cohort. Because of the dominant effect of age as a primary risk factor for cardiovascular disease (reflecting age-related incidence of coronary risk factors and accounting for duration of exposure), there is a low likelihood of identifying young patients with a high lifetime risk using the FRS. In fact, one study suggested that almost 70% of young men and women (defined as age 55 years in men and 65 years in women) who presented with acute MI as their first manifestations of CHD were classified as low risk by FRS [7]. As a 10-year model, the FRS is ideal for identifying patients who are at increased short-term risk for future incident coronary events but does not accurately reflect the effect of risk factor exposure over time and the overall lifetime risk of coronary disease particularly among young patients. This is illustrated by a recent study from the Framingham cohort in which the lifetime rate of development of CHD was compared to the 10-year prediction rates for various age groups [8]. It was found that younger subjects in the lower risk groups who had a very low 10-year risk of CHD still had a substantial lifetime risk for CHD. As an example, 50-year-old men in the lowest risk tertile had a 10-year cumulative risk of 1 in 25 but had a lifetime risk of 44%, which was similar to that observed in high-risk patients (54%).

FRS 10–20%

Lipid lowering therapy if LDL 130 mg/dl

CHD equivalent

FRS 20%

Lipid lowering therapy if LDL 100 mg/dl

The FRS is also limited by its lack of inclusion of other potential risk predictors of coronary disease, such as family history of premature coronary disease. A family history of premature coronary disease is a widely accepted risk factor for the development of coronary disease. In an analysis of the Framingham cohort by Lloyd-Jones et al a validated positive family history of premature coronary disease conveyed a 2-fold increased risk for future coronary events in men and a 70% increase in women [9]. Lastly, due to the relatively homogenous demography of the Framingham cohort (predominantly a white middle-class population), the results of the FRS are most applicable to Caucasians and may be inaccurate when considering other ethnic groups [10–12]. Although performing well for white and black men and women, one study showed that FRS overestimated the cardiac event rate for Japanese American men, Hispanic men, and Native American women [13]. Realizing that the FRS underestimates the lifetime incidence of CHD, a new refined risk assessment model would be helpful in guiding aggressive primary prevention while limiting unnecessary therapy. Presymptomatic testing using noninvasive cardiovascular imaging has emerged as a potential tool to add incremental prognostic value beyond that predicted by standard cardiovascular risk factors.

jâ•…C OR ONARY ARTERY CALCIUM SCORING The association between vascular calcification and vascular disease has long been appreciated by pathologists. Calcification of the coronary arteries is part of the atherosclerotic process, occurring in small amounts in early atherosclerotic lesions, and is found more frequently with advanced lesions and older age. The origins of radiographic detection of calcified coronary atherosclerosis began with cardiac fluoroscopy, which was a primarily qualitative technique. The development of electron beam computed tomographic scanning in 1984 permitted noninvasive quantification of coronary artery calcium (CAC).

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Noninvasive Atherosclerosis Imaging for Risk Stratification

Coronary calcium deposits have a high X-ray density, which is approximately 2- to 10-fold higher than the lowdensity adjacent noncalcified tissue and surrounding fat tissue. The area or density method of coronary calcium quantitation, originally known as the Agatston score, is the most widely adopted method of quantifying CAC. This unitless measurement is derived from the product of the area of calcification (mm2) and its X-ray coefficient, a Â�measure of maximal density that is measured in Hounsfield units (HU) (Figure 19.2). During the scan, approximately 40 axial slices, 3 mm in thickness, are obtained within seconds, delivering a relatively low effective radiation dose estimated at approximately 1 milli-Sievert (average annual background radiation exposure in the United States is 3–5 mSv). Although the advantage of Electron Beam Computed Tomography (EBCT) is its temporal resolution, lower spatial resolution limits this scanner from cardiac CT applications beyond coronary calcium quantitation. Subsequently, rapid developments in multidetector computed tomography (MDCT) leading to improved temporal and spatial resolution allowed for its use as an alternative to electron beam computed tomography for quantification of epicardial CAC. Presently, based on similar results in coronary calcium scoring with these 2 methods, although the majority of studies examining the prognostic implications of CAC have been conducted with EBCT, it is implied that MDCTgenerated CAC scores have similar significance [14]. Rationale of CAC Scoring for Risk Assessment Although coronary calcium is observed more extensively in atherosclerotic plaques associated with stable angina pectoris, patients with elevated CAC have higher incident rates of myocardial infarction and cardiac death [15]. This paradox can be readily explained by the fact that patients with a high burden of calcified plaque are also more likely to have noncalcified plaque that is more prone to rupture, and thrombosis and pathologic data suggest that prior subclinical plaque ruptures presage subsequent plaque calcification during healing. Although CAC detection does not specifically predict a stenotic or rupture-prone lesion [16,17], its correlation with overall atherosclerotic disease burden has been well established [18,19]. The ability to detect and quantify CAC as an early marker for subclinical atherosclerosis is the cornerstone of its role as a risk stratification tool in preventive cardiology. The limited ability of the FRS to identify those patients at high risk for CHD was illustrated in a report of 1611 asymptomatic subjects who underwent CAC screening. Using the guideline recommendations for lipidlowering therapy, 59% of subjects with a CAC score .400 and 73% with a score .75th percentile would not have qualified for pharmacotherapy [20]. Recent research indicates that a sizable proportion of the screened population

3 01

2 if 200 HU2 CT ,300 HU 3 if 300 HU2 CT ,400 HU 4 if 400 HU2 CT Other methods for quantification of coronary calcium include the mass score and volume score. F ig ure 1 9 . 2 â•… The Agatston method of calculating coronary artery calcium. A focus of coronary calcium is commonly defined with the scan matrix as the presence of 3 contiguous voxels with a Hounsfield density of 130 or greater. In this figure, the Hansfield unit (HU) density of coronary calcium typically is much greater than 130, but a range of values exists within different atherosclerotic plaques. For each coronary artery, a region of interest (ROI) is drawn around each calcified lesion. The area, A, of the ROI is determined. A weighting factor, w, is assigned based on the degree of attenuation as assessed by HU. The Agatston score, S, is computed as the product of the weighting factor and the area:

S 5 w · A. The score for all lesions in all coronary arteries is summed to determine the total calcium burden. w 51 if 130 HU2 CT ,200 HU

will have their FRS risk status reclassified using calcium scoring. For example, in the Prospective Army Coronary Calcium Project, roughly 1 in 10 low-risk men were classified to intermediate clinical risk after calcium scanning. This has been popularized as the concept of arterial age and is available using an online risk calculator from the Multi-Ethnic Study of Atherosclerosis found at www .mesa-nlhbi.org.

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jâ•… Table 19.1â•… Distribution of coronary artery calcium scores for women and men across different age groups

Percentiles by Race

Women, n

Men, n

Age, y

Age, y

45–54

55–64

65–74

75–84

45–54

55–64

65–74

75–84

White, n

379

356

379

â•‡ 194

321

325

â•‡ 375

â•‡ 174

25th

â•‡â•‡ 0

â•‡â•‡ 0

â•‡â•‡ 0

â•‡â•‡ 20

â•‡â•‡ 0

â•‡â•‡ 0

â•‡â•‡ 21

â•‡ 103

50th

â•‡â•‡ 0

â•‡â•‡ 0

â•‡ 13

â•‡ 106

â•‡â•‡ 0

â•‡ 28

â•‡ 145

â•‡ 385

75th

â•‡â•‡ 0

â•‡ 16

119

â•‡ 370

â•‡ 22

155

â•‡ 540

1200

90th

â•‡â•‡ 8

102

391

â•‡ 921

110

452

1345

2933

95th

â•‡ 31

209

674

1535

207

743

2271

4619

Prognostic Value of CAC Multiple prospective studies have shown that high CAC scores are independently associated with increased risk for adverse coronary events. In a meta-analysis by Pletcher et al, it was found that the CAC score was associated with an increase in the risk for future CHD risk [21]. CAC scores were reported in 1 of 4 categories: no detectable CAC, low risk with a score of 1 to 100, medium risk with a score of 101 to 400, and high risk with a CAC score of .400. Figure 19.1 shows the adjusted odds ratios comparing the 3 positive groups to those with no detectable CAC. Increasing CAC scores carry progressively higher odds ratios, with scores .400 having an odds ratio that is 10 times higher than those found in the normal group. The authors further found that the relative risks reported by the 4 studies were between 4.3 and 17.0 for individuals in the high CAC score (.400) (Table 19.1). These relative risks are generally higher than standard risk factors such as the presence of diabetes, use of tobacco, extreme values of LDL or HDL, or blood pressure, which individually confer a relative risk of 1.5 to 3.4. Early controversy on whether coronary calcium predicted hard cardiovascular events (myocardial infarction or cardiac death) has resolved with the publication of higher quality studies in larger patient cohorts [22–25]. The largest observational series to date of more than 25 000 consecutive asymptomatic patients referred for CAC scanning confirm these findings [26]. With a mean follow-up of 6.8 years, this study showed that CAC is an independent estimator of all-cause mortality and that patients without CAC experienced an extremely low event rate, with a 12-year survival of 99.4%. Conversely, patients with CAC scores of .1000 had a 12-year survival rate of 76.9%. Most studies evaluating the predictive value of CAC have used absolute values of the calcium score, although few

asymptomatic patients who undergo screening have calcium scores in the range that is most predictive of future cardiac events. In one series, for example, only 7% of a 632-patient screening population had calcium scores .400 [27]. Alternatively, a calcium score .75 percentile for age and gender may be a better predictor of future cardiac events. Table 19.2 displays the percentile strata of CAC for both men and women across different age groups [28]. For any given coronary calcium score, a greater number of calcified coronary vessels predicts worse cardiovascular outcomes [26]. The Clinical Application of CAC in the Asymptomatic Patient Bayesian theory relates the post-test likelihood to the pretest probability for the particular patient undergoing a given test with defined test operating characteristics. For example, coronary calcium in a low-risk (eg, by the FRS) patient would not significantly affect post-test prediction for future events in the short term. Conversely, a negative calcium scan in an otherwise high-risk patient would not reduce the risk to a level at which preventive measures would be withheld. The value of CAC appears to be in patients with an intermediate pretest probability as predicted by FRS. In the South Bay Heart Watch study, Greenland et al concluded that a high CAC score was predictive of high risk among patients with FRS greater than 10% (intermediate risk) but not in patients with an FRS of less than 10% (low risk) [29]. Furthermore, recent data from additional reports provide further support that CAC scoring adds incremental prognostic value for patients with intermediate risk by FRS. As seen in Figure 19.3, Â�intermediate-risk patients with CAC greater than 400 would be expected to have event rates similar to CHD equivalent (10-year risk of greater than 20%). In the recent ACCF/ AHA Consensus Document, the Task Force committee

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jâ•… Table 19.2â•… Summary of prospective trials evaluating CIMT and incident coronary events in patients without known coronary heart disease CHD Patient details CIMT increment (mm)

Odds ratio Study (CI)

CIMT measurement

Clinical Events

Follow-up (y)

Age (y)

Gender

KIHD [5] 1.11 (1.06–1.16)

CCA/carotid

Fatal/nonfatal

1m–3y

42–60

Men

0.1

4–7

45–64

Men

0.19

Women

0.19 0.2

Bifurcation

MI

ARIC [6] 1.36 (1.23–1.51)

CCA/ICA/carotid

Coronary death

1.69 (1.50–1.90)

Bifurcationb

MI

CHS [14] 1.46 (1.33–1.60)d,e

CCA/ICA

MI/stroke

6.2

.65

Men and Women

Rotterdam [25] 1.56 (1.12–2.18)g

CCAf

MI/stroke

2.7

.55

Men

0.163

Women

0.163

a

c

Study 1.44 (1.00–2.08)g

CIMT, carotid intima-media thickness; KIHD, Kupio ischemic heart disease; CCA, common carotid artery; MI, myocardial infarction; ARIC, atherosclerosis risk in communities study; ICA, internal carotid artery; CHS, cardiovascular health study. a Mean CIMT. b Mean far wall, internal carotids, and bifurcation. c Mean of CCA and ICA. d The odds ratio stated is risk for MI and coronary death only. The odds ratio for MI and stroke was 1.47 (1.37–1.67). e CCA CIMT. f Mean CCA. g The odds ratio stated is for risk of MI only.

concluded that it was reasonable to consider CAC measurement in patients with intermediate risk by FRS, with the assumption that such patients with high CAC would be reclassified to a high-risk status and be treated with aggressive preventive therapy accordingly [30]. The committee did not recommend the use of CAC scoring in low- and high-risk populations. This Â�recommendation is in accord with other society guidelines anticipated in 2010 indicating that coronary calcium testing is a useful approach in

individuals at intermediate (Figure 19.4) or low cardiovascular risk in the setting of a family history of heart disease. Figure 19.5 offers an example algorithm employing CAC in the risk stratification of asymptomatic patients for CHD. Serial CAC testing is presently not recommended due to lack of understanding of the independent relationship to CHD outcomes. Preliminary data suggest that a calcium score progression of 15% per year may be

Summary RR Ratio CACS

RR (95% CI)

Events/N Higher Risk Low Risk*

Average Risk

1–112

1.9

(1.3−2.8)

67/9,514

45/12,163

0.001

Moderate Risk

100–400 4.3

(3.1−6.1)

110/5,209

19/11,817

0.0001

High Risk

400–999 7.2

(5.2−9.9)

182/3,940

49/8,649

0.0001

Very High Risk

1,000

(4.2−27.7) 14/196

6/905

0.0001

10.8

P

0.01

0.01

0.1

1

10

100

0.1

1

10

100

Lower Risk

Higher Risk

F igure 1 9 . 3 â•… Adjusted odds ratios comparing risk of a coronary heart disease event in persons with low (1–100), medium (101–400), and high

(.400) coronary artery calcium scores to persons without calcification. Error bars indicate 95% confidence interval. From Greenland et al. ACCF/ AHA Expert Consensus Document on Coronary Artery Calcium Scoring, JACC Vol. 49, No. 3, 2007: 378–402.

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Low Risk FRS 10%

Intermediate Risk FRS 10–20%

High Risk FRS 20%

CAC scoring not indicated

Consider CAC scoring

CAC scoring not indicated

Consider statins if LDL 160

CAC75 percentile for age/gender

Consider statins if LDL 100

CAC 75 percentile for age/gender

Consider statins if LDL 130

F igure 1 9 . 4 â•… A 64-year-old man presented for pre-exercise physical

evaluation. Cardiac risk factors included prehypertension and low high density lipoprotein cholesterol (HDL-C). The calculated 10-year Framingham risk score was 16%. Axial view multidetector noncontrast computed tomography images (2.5 mm thick, 120 kV, 100 mAs) shown in thick section with coronary calcium in the left main, left anterior descending, and left circumflex arteries. The total coronary calcium score was 733 units quantified by the area–density method. Quantitation of coronary calcium is typically performed on 2.5 mm axial slices, using the area and density (Agatston) method.

associated with a worse prognosis [31–33]. Further work is needed in this area. The use of cardiac CT imaging as a surrogate in therapeutic drug trials to identify agents that lead to CAC stabilization has been disappointing. Most notably statin therapy [34] and the intensity of statin treatment [35] have not been associated with slowed CAC progression. These data further limit the value of serial CAC scanning as a surrogate to tailor individual patient treatment. CAC and Future Challenges Despite the potential benefits of CAC screening, there are a few limitations that challenge its widespread adoption in the risk assessment of CHD. First, it has not been proven that instituting pharmacological therapy in asymptomatic patients with CAC ultimately improves outcomes. However, data from the Prospective Army Coronary Calcium study showed that statin and aspirin usage are strongly influenced by coronary calcium within a screening cohort under community-based care [36]. Among 1620 men followed for up to 6 years after coronary calcium screening, the use of statin and aspirin was significantly increased 3.5-fold in subjects with coronary calcium independent of other coronary risk factors. Furthermore, the use of aspirin and statin combined was 7-fold more likely (Figure 19.6). Interestingly, coronary calcium also influenced the prescription of statins in subjects relative to

F igure 1 9 . 5 â•…Implementing coronary artery calcium in risk stratifying asymptomatic patients for lipid therapy.

National Cholesterol Education Program guidelines such that statins were more commonly provided to all patients, regardless of whether the LDL cholesterol was above or below target. These data provide the first indication that community-based preventive cardiology management can be meaningfully altered. Whether coronary calcium scanning can be reasonably extended to low-risk patients to refine lifetime risk of CHD is an area of active study. Lastly, the cost-effectiveness of presymptomatic testing with coronary atherosclerosis imaging has not been well defined, but it is likely to be more dependent on the Â�subsequent therapeutic decisions and medical adherence than the test itself. Atherosclerotic disease burden often varies from a patient’s chronological age, leading to the concept of Â�identifying vascular age as an alternative for integration of CAC with the FRS. Shaw et al used CAC to estimate the number of life years lost (calcium-adjusted age) in 10â•›377 asymptomatic individuals referred for electron beam tomography screening who were followed for 5 years for all-cause mortality [37]. In linear prediction models, a calcium score ,10 resulted in a reduction in observed age by 10 years in subjects older than 70 years, whereas a calcium score .400 added as much as 30 years of age to younger patients. Furthermore, using calcium adjustments to age, 55% of those with a previously low-risk FRS were escalated to intermediate risk (P , .0001), whereas 45% of those with an unadjusted intermediate FRS were reclassified as high risk (P , .0001). CAC-adjusted age was a better predictor of mortality than observed age, leading to the conclusion that an integrated risk scoring system employing an individual’s biological age as determined by CAC instead of chronological age would likely refine the risk assessment process.

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Prevalence of Statin Use 60 50

Percent

40 Calcium = 0

30

Calcium 0

20 10

Ye

ar

6

5 ar Ye

ar Ye

Ye

Ye

4

3 ar

2 ar

1 ar Ye

Ba

se

lin

e

0

Follow-up Year Prevalence of Aspirin Use 60 50

Percent

40

Calcium = 0

30

Calcium 0

20

F igure 1 9 . 6 â•… Incidence of provision of

statin and aspirin over 6 years of communitybased follow-up among 1620 male participants of the Prospective Army Coronary Calcium Project.

10

6 ar Ye

5 ar Ye

4 ar Ye

3 Ye

ar

2 ar Ye

1 ar Ye

Ba

se

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e

0

Follow-up Year

jâ•…C ORONARY MULTIDETECTOR COMPUTED TOMOGRAPHY ANGIOGRAPHY The presence of CAC is associated with increased plaque burden and increased cardiovascular risk. A potential concern, however, is the presence of isolated noncalcified plaques in the setting of a CAC score of zero. Theoretically, the identification of patients with noncalcified plaques (Figure 19.7) or mixed plaques (containing both calcified and noncalcified elements, Figure 19.8) could possibly improve or refine risk stratification. With the advent of MDCT contrast angiography, direct visualization of coronary plaque is now possible. This has stimulated interest in the angiographic evaluation of coronary plaque as a potential tool for risk assessment in CHD. The occurrence of isolated noncalcified plaque was recently estimated in a cohort of 161 asymptomatic patients with intermediate risk by FRS [38]. In this study, 6.2% of patients had solely noncalcified plaques as their only manifestation of coronary atherosclerosis. Knez et al

studied 2115 consecutive symptomatic patients who underwent both CAC and coronary angiography [39]. No calcium was found in 7/872 (0.7%) men and 1/383 (0.03%) women who had significant luminal stenosis. Seven of these 8 patients were younger than 45 years of age. Several other reports indicate that CAC is not sensitive in patients younger than 45 years of age, leading to the hypothesis that MDCT, particularly among selected subgroups (young patients, intermediate-risk patients with no evidence of CAC), may be useful. However, it should be noted that a zero calcium score is associated with an extremely low (0.2% per year) risk of cardiovascular events over 3 to 5 years [26]; thus, the clinical value of detection of noncalcified plaque remains unknown. Methods of quantitation of noncalcified plaque are in development, with the requirement for high spatial and temporal resolution. Leber et al compared the assessment of total coronary plaque volume by 64-slice MDCT to IVUS, considered the gold standard for plaque quantification [40]. Although MDCT underestimated plaque relative to IVUS (54/65 plaques correctly identified), correlation for

306

Multimodality Imaging in Cardiovascular Medicine

A

F igure 1 9 . 8 â•…Large mixed plaque consisting of a small calcified plaque surrounded by a large area of noncalcified atherosclerosis, as shown on coronary computed tomography angiography.

B

C F igure 1 9 . 7 â•…Coronary computed tomography (CT) angiography

images of noncalcified plaque from the proximal right coronary artery (panel A). The CT density of the plaque was .90 HU, consistent with fibrous plaque (panel B). Outward arterial remodeling was seen, with a remodeling index (comparison of proximal arterial diameter and lesion arterial diameter) of 1.37 (panel C).

determination of overall plaque volume was good (R2 5 0.69). The major obstacle for plaque identification and quantification is the edge definition of the outer vessel boundary, which makes it difficult to distinguish between plaque and soft tissue. Even with the later generation scanners with greater coverage, the limited spatial resolution of approximately 0.4 mm prevents an exact separation of lumen, plaque, and vessel wall and the subsequent detection of very early stages of coronary atherosclerosis. Furthermore, limits of temporal resolution create the potential for false-positive findings due to motion artifact/ blurring. Further characterization of noncalcified plaques is proposed as an additional risk stratification method. Due to the different X-ray density profiles of the various plaque components, MDCT can potentially distinguish unstable, and presumably lipid-laden, coronary plaques from more stable, fibrous plaques. Fibrous plaques are proposed to display mean attenuation values of approximately 90 HU, whereas plaques with large lipid-rich cores have lower attenuation patterns (30–50 HU) [41]. However, substantial overlap of the CT densities of fibrous and soft plaques limits their consistent differentiation. Beyond CT density of plaque, other findings suggestive of high-risk morphological features of coronary plaques include the presence of outward remodeling of the vessel wall or spotty calcifications (Figure 19.9) [42]. To date, there is no evidence that plaque characterization by either HU or by the presence of high features with MDCT has any meaningful impact on risk stratification or patient management beyond the detection of coronary calcium alone. Several features of MDCT limit enthusiasm for its use as a cardiovascular risk assessment tool in presymptomatic individuals. Increased clarity of images provided by new generation scanners requires radiation doses ranging from 4.8 to 21.6 mSv [43]. However, the relative concern over high levels of accuracy and radiation exposure with cardiac CT is decreasing based on the evolution in CT detector

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3 07

F igure 19.9â•… Noncontrast computed tomography angiograms from 2 different patients showing the different appearance of spotty versus large calcified plaques. (Left) spotty diffuse calcification through the proximal left coronary artery; (right) large calcified lesion in the proximal left anterior descending coronary artery. Outcomes data suggest that the prognosis of spotty calcifications is worse relative to the future risk of acute coronary syndromes.

technology and reconstruction algorithms, in parallel with rapidly decreasing radiation exposure requirements for high-quality cardiac CT images. Other issues to consider are the need for intravenous contrast and the potential for needless follow-up radiographic studies for incidental findings [44]. Furthermore, there is the potential that physicians may prescribe statins to asymptomatic patients based solely on the presence of plaque, ignoring more extensively studied and validated parameters of risk assessment such as CAC. Given these limitations, screening asymptomatic patients for plaque using MDCT is considered an inappropriate application of the technology.

jâ•… CAROTID INTIMA-MEDIA THICKNESS Carotid intima-media thickness (CIMT) is associated with known cardiovascular risk factors and accurately detects the presence and extent of atherosclerosis. This relationship allows for its use as a noninvasive marker of early, preclinical atherosclerosis. CIMT is related to CHD risk factors, future cardiovascular events, and atherosclerosis elsewhere in the vascular system. Although it is primarily used as a research tool in epidemiologic trials and in clinical trials assessing the therapeutic effect of antiatherosclerotic drugs, it has the potential of a simple, low-cost, safe test to have a clinical role in the primary prevention of CHD. Specific imaging advantages of CIMT include its noninvasive nature without a requirement for ionizing radiation or intravenous contrast and the low likelihood of incidental scan findings. Definition and Measurement of CIMT The arterial wall consists of 3 layers—the intima, the media, and the adventitia. Clinically detectable atherosclerosis initially consists of gradual thickening of the intima and media layers. Through direct visualization of the arterial wall of a superficial artery such as the carotid artery, B mode ultrasound can measure this thickening as the

combined thickness of the intima and media, as these 2 Â�layers cannot be reliably distinguished using ultrasound. The intima-media thickness, defined as the thickness between the intimal-luminal and the medial-adventitial interfaces, is measured (Figure 19.10). Sonograms are generally obtained with the patient in the supine position and with their head turned slightly to the contralateral side. Longitudinal images of the carotid artery focusing on the imaging target of interest (eg, far wall of the common carotid artery) are acquired with Â�linear digital ultrasound probes at high frequency (10–13 MHz). Due to systolic arterial expansion and the resultant CIMT thinning, digital images are acquired from an end-diastolic frame of the cine-loop recording, electronically stored and transferred to a workstation for quantification. The Â�intimal-luminal and medial-adventitial borders can be manually or automatically traced (using edge-detection software) to measure the CIMT (Figure 19.7). Measurement of the far wall of the distal 1 cm of the common carotid artery is preferred over measurement of other segments such as

Bulb

Lumen Far wall IMT

F igure 1 9 . 1 0 â•…Carotid ultrasound image (10 MHz) of the distal

common carotid artery. The 2 arrows represent the intimal-luminal and medial-adventitial interfaces, which collectively border the Carotid intimamedia thickness (CIMT). In this example, CIMT was reported as the mean thickness over the distal 1 cm of the far wall of the common carotid artery.

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the carotid bulb or internal carotid artery, due to its greater reproducibility, and completeness of evaluation. Carotid IMT in different segments is equally predictive of future cardiovascular events [45–49]. Several studies have verified the reproducibility of CIMT measurements. Most of the measurement variability in CIMT is caused by differences between observers, whereas the within-observer variability over time appears very small [50]. Normal CIMT values have been defined based on their distribution within a general healthy population and have been classified according to age and gender [51,52]. CIMT increases with age and, on average, is slightly greater in men than that in women. Slight racial differences have also been reported for CIMT, being highest in African Americans, least in Hispanics, and intermediate in Caucasians [46,53,54]. The definition of the upper limit of normal is arbitrary but is frequently set at the 75th percentile of CIMT distribution (Figure 19.11) for the determination of increased relative CHD risk. Alternatively, epidemiological studies suggest that a value of IMT at or above 1 mm is associated with a significantly increased absolute risk of CHD [51]. Reliance on a single absolute threshold abnormality will result in underdetection of disease in younger individuals and overdetection in older individuals. Surrogate Marker for Atherosclerosis Risk The Muscatine study followed 725 individuals from childhood to early adulthood (aged 33–42 years) and found that CIMT was associated with the childhood presence of cardiovascular risk factors, especially total and LDL cholesterol in both genders, and diastolic blood pressure in women [55]. Raitakari et al also confirmed an association between childhood cardiovascular risk factors,

1.4

Men Women

Mean CIMT (mm)

1.2 1 0.8 0.6 0.4 0.2 0

35

45

55

65

75

85

Age F igure 1 9 . 1 1 â•… Approximate 75th percentile values for the common carotid intima-media thickness by age and gender.

namely, LDL cholesterol, systolic blood pressure, and smoking, and CIMT measured 21 years later [56]. In this study, adolescents with these cardiac risk factors had an approximately 0.1 mm greater CIMT as adults compared to those Â�without risk factors. In the Bogalusa Heart Study, metabolic Â�syndrome during childhood was associated with a 2.5-fold increased likelihood of having a CIMT in the highest quintile [57]. In addition to reflecting an individual’s past exposure to cardiovascular risk factors, CIMT is associated with prevalent cardiovascular disease and future cardiovascular risk. The Atherosclerosis Risk in Communities (ARIC) study demonstrated a prevalence of myocardial infarction in individuals in the highest quartile of CIMT of 5% [58]. In the Cardiovascular Health Study (CHS), the odds ratio for symptomatic CHD was 2.8, comparing the highest with the lowest quartile of CIMT [59]. The relationship between CIMT and incident CHD events first became evident in the Kupio Ischemic Heart Disease (KIHD) risk factor study in which, for every 0.1 mm increment of CIMT, the risk of future myocardial infarction in Finnish men increased by 11% [60]. For CIMT values .1 mm, there was a 2-fold greater risk for acute myocardial infarction over 3 years. The ARIC study provided further support, noting that for every 0.19 mm increment in CIMT, the risk of death or myocardial Â�infarction increased by 36% in middle-aged patients Â�(45–65 years of age) [51]. The CHD risk was almost 2-fold greater in men with mean CIMT .1 mm and even greater in women (risk ratio of 5). Not all studies, however, have shown gender differences in the predictive value of CIMT. For example, the Rotterdam study found that the risk of CHD events and CIMT was similar among men and women [61]. The association between CIMT and incidence of myocardial infarction and stroke has been noted in older populations as well. In CHS, the adjusted relative risk for myocardial infarction was 3.6, holding true for both patients with and without known cardiovascular Â�disease [62] (Table 19.2). Because CIMT testing at any given moment reflects the integrated effect of cumulative risk factor exposure, it is primarily a reliable predictor of future CHD risk in those patients whose risk factor status (including lifestyle Â�behavior) is stable. However, in patients undergoing risk factor modification, CIMT testing likely will not Â�accurately reflect current risk factor burden and subsequently may be a poor predictor of outcome. It has been proposed that CIMT progression in such individuals might be a Â�better index of risk for future CHD [63]. In the Cholesterol Lowering Atherosclerosis Study (CLAS), men who had undergone previous coronary artery bypass graft surgery were treated with colestipol and niacin [64]. An annual CIMT increase .0.033 mm per year was associated with a 2.8-fold increased risk of myocardial infarction, death, or need for revascularization over 7 years. CIMT and Â�progression of CIMT predicted CHD risk beyond that predicted by measurements of coronary atherosclerosis by angiography and lipid measurements [65].

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The Â�strategy of using serial CIMT studies as a surrogate of atherosclerosis effects has been used in multiple clinical lipid trials (Table 19.3). In a placebo-controlled study of statin monotherapy (REGRESS), a 0.05 mm annual reduction in mean carotid and femoral artery intima-media thickness led to an absolute risk reduction of 10% over 2 years in the incidence of cardiac events [66]. Trials studying Â�niacin have shown the particular effectiveness of CIMT as a Â�surrogate. ARBITER 2 [67] and 3 [68] defined the Â�ability of Â�niacin-induced increases in HDL-C to induce CIMT regression. Most recently, ARBITER 6-HALTS showed the superiority of niacin over ezetimibe, when added to statin monotherapy [69]. Niacin led to significant regression of CIMT, which was detectable using a highly precise CIMT protocol in a time horizon as short as 8 months. In contrast to use in study groups, the serial use of CIMT for individual patient assessments is difficult unless performed after an extended time interval to permit discrimination of true CIMT progression from measurement variability.

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Ultrasound plaque composition using gray-scale and integrated backscatter within carotid ultrasound images has been correlated to the extent of lipid deposition within plaques [70]. Individuals with stable CHD and low-intensity (lipid rich) carotid plaques are predicted to have higher risk of subsequent recurrent CHD events [71]. Standardized methods of determining ultrasonic plaque composition are needed. Role of CIMT in Risk Assessment CIMT has favorable characteristics as a CHD screening tool. It is noninvasive, quantitative, and correlates with clinical outcome. Furthermore, it is repeatable and demonstrates satisfactory interscan and interobserver reproducibility, which may allow for assessment of atherosclerotic progression over time [72]. Because coronary calcium may be absent in young individuals in whom the concerns on radiation exposure is heightened, CIMT testing may offer

jâ•… Table 19.3â•… Summary of trials demonstrating the effects of lipid therapy on CIMT in patients with known CHD Mean Change in CIMT(mm/y) Trial

Details

Patients Randomized Intervention

Length of Study (y)

Treatment

Placebo

Pvalue

Pravastatin 10-40mg/day Pravastatin 40mg/day

3

10.0295a

10.0456a

0.03

2

0.05b

0b

0.0085

Patients with CAD and elevated LDL-C Male patients with CAD and normal to moderately elevated total cholesterol

151

MARS46

Patients with CAD and moderately elevated total cholesterol

188

Lovastatin 80mg/day

2

0.038a,d

10.019a,d

0.001

LIPID47

Patients with CAD and moderately elevated total cholesterol

522

Pravastatin 40mg/day

4

0.014c,d

10.048c,d

î•¬0.001

CLAS27

Male patients who had undergone coronary artery bypass surgery

188

Colestpol and niacin

4

0.026c

10.018c

î•¬0.05

ARBITER48

Patients with CAD and who met NCEP-II criteria for statin therapy

161

Atorvastatin 80mg

1

0.034a

10.025a,e

0.03

ARBITER-II49 Patients with CAD already taking statins

167

Extended release niacin

1

10.014a

10.044a

0.08

ARBITER 669 On statins, LDL î•¬100 HDL î•¬ 50–55 mg/dL

363

Extended release or ezetimibe

14 months

0.0142

0.0007 (ezetimibe)

0.01

PLAC-II45 REGRESS52

255

MARS, Monitored Atherosclerosis Regression Study; LIPID, Long-term Intervention with Pravastatin in Ischaemic Disease; ARBITER, Arterial Biology for the Investigation of the Treatment Effects of Reducing cholesterol; CAD, coronary artery disease; PLACII, Pravastatin, lipids, and antherosclerosis in the carotid arteries a CIMT of the CCA b Mean intima media thickness of femoral and carotid arteries c CIMT of the right CCA d Mean change in CIMT during study period e Pravastatin 40mg served as comparison group

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specific advantages in the young. Individuals with greater CIMT appear to be at greater risk for coronary calcium progression, and the 2 assessments can be complementary in the detection of CHD risk. Many patients, particularly young adults, are classified as low to intermediate risk despite the presence of metabolic syndrome, which has clearly been shown to be associated with increased CIMT and risk for atherosclerotic progression. This was assessed by Baldassarre et al who investigated whether CIMT could be combined with the FRS to improve the predictability of cardiovascular events in dyslipidemic patients who are at low or intermediate risk [73]. Both FRS and CIMT proved to be independent outcome predictors with a hazard ratio of 6.7 in patients with an FRS of 10% to 20% and elevated CIMT (.60th percentile for men or 80th for women). This category of patients, who currently are not aggressively treated based on current guidelines, proved to have similar risk as patients with FRS of 20% to 30%. Stein et al further explored the effect of age on the calculated FRS. By substituting CIMT-determined vascular age for chronological age, they reclassified cardiovascular risk Â�according to FRS in patients without known CHD [74]. The substitution of vascular age for chronological age increased the Framingham 10-year risk score from 6.5% to 8.0% (P , .001). Of the subjects initially deemed to be intermediate risk, 35.7% were reclassified as higher risk based when CIMT-determined vascular age was applied. Although interesting, this strategy has not been tested in a large trial with hard clinical endpoints. Nevertheless, the findings of these studies are consistent with recommendations from Prevention Conference V, which stated that CIMT measurement can be considered for further clarification of CHD risk [75].

jâ•… MAGNETIC RESONANCE IMAGING Cardiovascular magnetic resonance (CMR) imaging offers the ability to detect subclinical arterial and coronary plaque [76,77]. Instead of using ionizing radiation, CMR uses proton excitation with a radiofrequency pulse in the setting of a high local magnetic field, usually around 1.5 Tesla. Beyond identification and quantitation of plaque, a specific potential advantage of CMR plaque assessment is the differentiation of the tissue content within atheroma, on the basis of magnetic properties of protons in water, by use of a range of imaging algorithms to optimize contrast and Â�proton density. By employing a multicontrast approach with high-Â� resolution black-blood spin-echo and fast spin-echo–based CMR sequences, blood flow signal can be rendered black, allowing characterization of the adjacent vessel wall and differentiation of fibrocellular, lipid-rich, and calcified regions of atherosclerotic plaque [78,79]. Furthermore, quantification of plaque size and detection of fibrous cap integrity and the presence of lipid cores are possible [80–82].

Multimodality Imaging in Cardiovascular Medicine

Presently, limitations to the spatial and temporal resolution of CMR limit its application to large-vessel pathology such as aortic, carotid, and peripheral arterial disease [83,84]. The ability of CMR to potentially serve as a tool in risk assessment was first seen in the offspring cohort of the Framingham Heart Study who underwent T2-weighted black-blood thoracoabdominal aortic CMR scanning [85]. Plaque prevalence and all measures of plaque burden increased by age group and were greater in the abdomen than in the thorax for both sexes and across all age groups. Furthermore, it was significantly correlated with the FRS in both men and women. The composition of atherosclerotic plaques governs their vulnerability to rupture and hence their propensity to cause cardiovascular events. Due to its putative Â�ability to characterize plaque content, MR may have Â�important implications for the understanding and modification of atherosclerosis. It was recently demonstrated that Â�gadolinium-based contrast agents enhance the identification of the fibrous cap of atherosclerotic plaques, possibly through a greater distribution of the agent in the neovascularized areas of the cap [86]. The identification of highrisk atherosclerotic plaque with CMR may be aided in the future by the detection of specific molecular plaque components through targeted CMR contrast agents in vivo [87]. CMR may potentially add prognostic value of qualitative (eg, presence of thin fibrous cap) beyond quantitative (eg, plaque thickness) atherosclerotic measures, although further research is needed in this area. The characterization of the coronary epicardial vessels with coronary artery magnetic resonance angiography (CMRA) remains challenging. Despite numerous and ongoing technical improvements, difficulties in coronary imaging include smaller vessel caliber, cardiac and respiratory motion artifacts, vessel tortuosity, and limited temporal resolution. A large multicenter trial of patients who underwent CMRA and traditional coronary angiography revealed that primarily the proximal 3 to 5 centimeters of the major coronary vessels were deemed interpretable [88]. Currently, CMR is employed clinically in the evaluation of large-vessel pathology and in the research setting to assess vascular response to antiatherosclerotic therapy (Figure 19.12) as a clinical surrogate with high reproducibility. Further improvements in temporal and spatial resolution may enable coronary arterial wall imaging.

jâ•…B RA CH IAL ARTERY FLOW-MEDIATED DILATION Most noninvasive risk assessment tools are based on anatomical measures of atherosclerosis such as plaque burden or plaque composition. In contrast, brachial artery reactivity testing (BART) is a functional assessment of the arteries. An increase in shear stress on the surface of the

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Baseline

24 Months

F igure 1 9 . 1 2 â•… T2-weighted magnetic resonance images of descend-

ing aorta at baseline and 24 months of a patient treated with statin therapy [89]. After 24 months of lipid lowering therapy, there is a reduction in the hypodense signal (arrows), suggestive of plaque reduction of the lipid-laden component. Due to its ability to quantify and characterize plaque without ionizing radiation, magnetic resonance (MR) may emerge as a powerful noninvasive imaging tool for serial evaluation of progression and therapy-induced regression of atherosclerotic plaques.

endothelial cells results in activation of nitric oxide synthase and an increase in available nitric oxide, the predominant vasodilator in the arterial system. Nitric oxide plays a critical role in the atherosclerotic process, including platelet adhesion and aggregation, smooth muscle proliferation, and low-density lipoprotein uptake [90]. It is postulated that the degree of arterial vasodilation in the setting of a flow-mediated increase in shear stress acts as a surrogate for endothelial cell function, namely, the ability to produce and release nitric oxide. Endothelial dysfunction is characterized by a reduction in the bioavailability of nitric oxide and an impairment of endothelium-dependent vasodilation. Given the relationship between endothelial dysfunction and atherosclerosis, it is likely that the status of endothelial function may reflect the propensity of an individual to develop atherosclerotic disease, and thus, the presence of endothelial dysfunction may serve as a marker of an unfavorable cardiovascular prognosis. In BART, endothelial function of the peripheral artery is assessed by applying an increased hemodynamic shear stress during reactive hyperemia as a stimulus for the release of nitric oxide. During BART, a sphygmomanometric cuff

311

is placed around the arm, just above the antecubital fossa, of a resting patient. Baseline ultrasound images of the brachial artery are acquired using high-frequency ultrasound with a vascular transducer and built-in ECG capabilities. After inflation of the cuff to approximately 50 mm Hg above the resting systolic blood pressure for 5 minutes, the cuff is released, and ultrasound images are again obtained assessing the degree of vasodilation of the brachial artery 1 minute later, during the reactive hyperemic phase. Clear visualization of the luminal-intima interface of both the near and far walls of the brachial artery is essential. After identifying these boundaries with edge calipers, the operator can determine the diameter of the vessel using specialized software packages. The response of brachial artery reactivity is generally measured as the change in poststimulus diameter, as a percentage of the baseline diameter. It is critical that patients are instructed not to smoke or eat for at least 12 hours before testing and that testing is conducted in a quiet, temperature-controlled room. Several factors have been identified that can affect flow-mediated vascular response, including recent fat and caffeine digestion, drugs, temperature, and sympathetic stimuli [91,92]. A normal vasodilator response is generally considered when there is at least a 10% increase in the diameter of the brachial artery during the reactive hyperemic phase relative to baseline [93]. The response, however, tends to be significantly attenuated in men older than 40 years and women older than 50 years of age. The vasodilator response is also inversely dependent on the baseline brachial artery diameter [94]. Because the endothelium may be a target that integrates the damaging effects of traditional risk factors, it may serve as a potential indicator of cardiovascular risk. Endothelial dysfunction has been linked to dyslipidemia, hypertension, diabetes mellitus, smoking, aging, menopause, family history of premature atherosclerosis, and hyperhomocysteinemia [95–97]. Endothelial dysfunction represents an early stage in the atherosclerotic process, preceding the anatomical features of subclinical disease [98]. Thus, BART may be particularly useful in the risk stratification of younger populations in whom the sensitivity of other tests such as CAC is reduced. Emerging evidence suggests that brachial artery FMD may be an independent predictor of outcomes [99–101]. It is essential, however, to realize that the data correlating brachial artery FMD to coronary endothelial function and to CV outcomes are derived primarily from studies in individuals with manifest CV disease or at high risk for CV disease, with very limited information on low-risk and moderate-risk groups. Gocke et al preoperatively examined brachial artery vasodilation in 187 patients undergoing vascular surgery. Preoperative endothelium-dependent flow-mediated dilation was significantly lower in patients with a cardiovascular event (4.9%  3.1%) than in those without an event (7.3%  5%; P , .001) within the first 30 days of the postoperative period.

312

The major limitation of BART is the short-term biologic variability of the measurement. Due to the effects of dietary changes and phase of the menstrual cycle on BART, patient preparation is critical. Furthermore, protocols for assessing BART vary among laboratories and are operator dependent, decreasing the feasibility of this noninvasive tool to serve as a valuable screening tool for endothelial dysfunction in clinical practice [90,102]. Unlike other noninvasive assessments like CIMT, there is no proof that therapeutic improvement in endothelial function translates into lower cardiovascular morbidity and mortality, and further prospective trials are required to determine the suitability of BART to serve as a primary therapeutic endpoint. Currently, BART is utilized as a research tool but has limited clinical application.

jâ•…M OTIVATIONAL EFFECTS OF ATHEROSCLEROSIS IMAGING Atherosclerosis imaging has been postulated to motivate patient behavioral change. However, despite anecdotal and logical plausibility, the evidence to date fails to suggest a long term, durable, motivational effect of atherosclerosis imaging. Several survey studies using either cardiac computed tomography for the detection of coronary calcium [103,104], or carotid ultrasonography for the detection of intima-media thickness or plaque [105] have suggested that survey respondents among primarily referred populations report being motivated for healthy behavioral change with a common theme of increased perception of risk. In contrast, studies of actual behavioral change have yielded conflicting results. Although a study of carotid ultrasonography showed improved success at smoking cessation in smokers showing ultrasound evidence of carotid plaque [106], in general, biomedical aids to enhance smoking cessation have not been shown to be effective [107]. Two randomized trials of coronary calcium have also shown imaging to be ineffective in motivating behavioral change. In studies of coronary calcium screening among healthy middle aged military personnel (The Prospective Army Coronary Calcium Study) [108] and of postmenopausal women [109], there was no relationship between imaging and behavioral change or motivation after 1 year. These findings parallel the limited motivational impact that even definite cardiac events such as myocardial infarction have no long term patient behavior. Notably, within the factorial design of the PACC Project randomized trial, a randomization arm of a nurse case management approach to behavioral change was successful in stabilizing coronary risk, reducing the incidence of metabolic syndrome, and increasing patient motivation for change [108,110]. Thus, while the available data suggest against a large and directly attributable effect of atherosclerosis imaging on patient motivation, incorporating these data into a recurring clinical patient/physician relationship could lead to behavioral modification [111].

Multimodality Imaging in Cardiovascular Medicine

jâ•… CON CLUSION Standard CHD risk assessment with FRS is imprecise and leaves a large proportion of patients classified as intermediate, effectively underestimating the actual lifetime risk of CHD in a large group of patients. It is logical to conclude that using one or more of these noninvasive techniques, in addition to the risk models previously discussed, could improve the predictive power of the FRS with enhancements in sensitivity and specificity. An improved model could help to identify subjects whose lifetime risk of CHD may be underrepresented by the standard FRS, as well as improve the risk stratification to the large population of subjects in the intermediate risk category. Currently, plaque burden has been the most extensively studied variable of subclinical atherosclerosis. However, different imaging modalities have been proven to be inconsistent in the identification of high degrees of plaque burden and demonstrate poor correlation. For example, in a comparison of the overlap across CMR aortic plaque, CAC, and CIMT in the offspring cohort of the Framingham study, only 4% of men and 16% of women were classified as having high atherosclerosis on all 3 measurements [112]. Nevertheless, CAC scoring and CIMT testing remain the most accepted means of improving risk stratification from an evidence-based approach, while MDCT angiography, CMR, and BART await validation as measures of cardiovascular risk in prospective trials. Screening for subclinical atherosclerosis has been advocated for individuals at intermediate global risk for CHD. There is a need for an improved integrated risk scoring system with biological age as determined by CIMT and/or CAC replacing chronological age in the FRS. Future studies assessing outcome improvement and cost-effectiveness of these primary prevention efforts are warranted.

jâ•… REF ERENCES â•‡â•‡ 1. Lloyd-Jones DM, Larson MG, Beiser A, Levy D. Lifetime risk of developing coronary heart disease. Lancet. 1999;353(9147):89–92. â•‡â•‡ 2. Wilson PW, D’Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB. Prediction of coronary heart disease using risk factor categories [see comments]. Circulation. 1998;97(18):1837–1847. â•‡â•‡ 3. D’Agostino RB, Russell MW, Huse DM, et al. Primary and subsequent coronary risk appraisal: new results from the Framingham study. Am Heart J. 2000;139(2, pt 1):272–281. â•‡â•‡ 4. Lerner DJ, Kannel WB. Patterns of coronary heart disease morbidity and mortality in the sexes: a 26-year follow-up of the Framingham population. Am Heart J. 1986;111(2):383–390. â•‡â•‡ 5. NCEP Writing Group. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA. 2001;285(19):2486–2497. â•‡â•‡ 6. Ford ES, Giles WH, Mokdad AH. The distribution of 10-year risk for coronary heart disease among US adults: findings from the National Health and Nutrition Examination Survey III. J Am Coll Cardiol. 2004;43(10):1791–1796.

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â•‡â•‡ 7. Akosah KO, Schaper A, Cogbill C, Schoenfeld P. Preventing myocardial infarction in the young adult in the first place: how do the National Cholesterol Education Panel III guidelines perform? J Am Coll Cardiol. 2003;41(9):1475–1479. â•‡â•‡ 8. Lloyd-Jones DM, Wilson PW, Larson MG, et al. Framingham risk score and prediction of lifetime risk for coronary heart disease. Am J Cardiol. 2004;94(1):20–24. â•‡â•‡ 9. Lloyd-Jones DM, Nam BH, D’Agostino RB Sr, et al. Parental cardiovascular disease as a risk factor for cardiovascular disease in middle-aged adults: a prospective study of parents and offspring. JAMA. 2004;291(18):2204–2211. â•‡ 10. Brindle P, Emberson J, Lampe F, et al. Predictive accuracy of the Framingham coronary risk score in British men: prospective cohort study. BMJ. 2003;327(7426):1267. â•‡ 11. Empana JP, Ducimetiere P, Arveiler D, et al. Are the Framingham and PROCAM coronary heart disease risk functions applicable to different European populations? The PRIME Study. Eur Heart J. 2003;24(21):1903–1911. â•‡ 12. Marrugat J, D’Agostino R, Sullivan L, et al. An adaptation of the Framingham coronary heart disease risk function to European Mediterranean areas. J Epidemiol Commun Health. 2003;57(8):634–638. â•‡ 13. D’Agostino RB Sr, Grundy S, Sullivan LM, Wilson P. Validation of the Framingham coronary heart disease prediction scores: results of a multiple ethnic groups investigation. JAMA. 2001;286(2):180–187. â•‡ 14. Horiguchi J, Yamamoto H, Akiyama Y, Marukawa K, Hirai N, Ito K. Coronary artery calcium scoring using 16-MDCT and a retrospective ECG-gating reconstruction algorithm. AJR Am J Roentgenol. 2004;183(1):103–108. â•‡ 15. Schmermund A, Erbel R. Unstable coronary plaque and its relation to coronary calcium. Circulation. 2001;104(14):1682–1687. â•‡ 16. Haberl R, Becker A, Leber A, et al. Correlation of coronary calcification and angiographically documented stenoses in patients with suspected coronary artery disease: results of 1764 patients. J Am Coll Cardiol. 2001;37(2):451–457. â•‡ 17. Rumberger JA, Brundage BH, Rader DJ, Kondos G. Electron beam computed tomographic coronary calcium scanning: a review and guidelines for use in asymptomatic persons. Mayo Clin Proc. 1999;74(3):243–252. â•‡ 18. Rumberger JA, Simons DB, Fitzpatrick LA, Sheedy PF, Schwartz RS. Coronary artery calcium area by electron-beam computed tomography and coronary atherosclerotic plaque area. A histopathologic correlative study. Circulation. 1995;92(8):2157–2162. â•‡ 19. Sangiorgi G, Rumberger JA, Severson A, et al. Arterial calcification and not lumen stenosis is highly correlated with atherosclerotic plaque burden in humans: a histologic study of 723 coronary artery segments using nondecalcifying methodology. J Am Coll Cardiol. 1998;31(1):126–133. â•‡ 20. Nasir K, Michos ED, Blumenthal RS, Raggi P. Detection of highrisk young adults and women by coronary calcium and National Cholesterol Education Program Panel III guidelines. J Am Coll Cardiol. 2005;46(10):1931–1936. â•‡ 21. Pletcher MJ, Tice JA, Pignone M, Browner WS. Using the coronary artery calcium score to predict coronary heart disease events: a systematic review and meta-analysis. Arch Int Med. 2004;164(12):1285–1292. â•‡ 22. Arad Y, Goodman KJ, Roth M, Newstein D, Guerci AD. Coronary calcification, coronary disease risk factors, C-reactive protein, and atherosclerotic cardiovascular disease events: the St. Francis Heart Study. J Am Coll Cardiol. 2005;46(1):158–165. â•‡ 23. Greenland P, LaBree L, Azen SP, Doherty TM, Detrano RC. Coronary artery calcium score combined with Framingham score for risk prediction in asymptomatic individuals. JAMA. 2004;291(2):210–215. â•‡ 24. Taylor AJ, Bindeman J, Feuerstein I, Cao F, Brazaitis M, O’Malley PG. Coronary calcium independently predicts incident premature coronary heart disease over measured cardiovascular risk factors: mean three-year outcomes in the Prospective Army Coronary Calcium (PACC) project. J Am Coll Cardiol. 2005;46(5):807–814.

313

â•‡ 25. Vliegenthart R, Oudkerk M, Song B, van der Kuip DA, Hofman A, Witteman JC. Coronary calcification detected by electron-beam computed tomography and myocardial infarction. The Rotterdam Coronary Calcification Study. Eur Heart J. 2002;23(20):1596–1603. â•‡ 26. Budoff MJ, Shaw LJ, Liu ST, et al. Long-term prognosis associated with coronary calcification: observations from a registry of 25 253 patients. J Am Coll Cardiol. 2007;49(18):1860–1870. â•‡ 27. Raggi P, Callister TQ, Cooil B, et al. Identification of patients at increased risk of first unheralded acute myocardial infarction by electron-beam computed tomography. Circulation. 2000;101(8):850–855. â•‡ 28. Hoff JA, Chomka EV, Krainik AJ, Daviglus M, Rich S, Kondos GT. Age and gender distributions of coronary artery calcium detected by electron beam tomography in 35 246 adults. Am J Cardiol. 2001;87(12):1335–1339. â•‡ 29. Greenland P, LaBree L, Azen SP, Doherty TM, Detrano RC. Coronary artery calcium score combined with Framingham score for risk prediction in asymptomatic individuals. JAMA. 2004;291(2):210–215. â•‡ 30. Greenland P, Bonow RO, Brundage BH, et al. ACCF/AHA 2007 clinical expert consensus document on coronary artery calcium scoring by computed tomography in global cardiovascular risk assessment and in evaluation of patients with chest pain: a report of the American College of Cardiology Foundation Clinical Expert Consensus Task Force (ACCF/AHA Writing Committee to Update the 2000 Expert Consensus Document on Electron Beam Computed Tomography) developed in collaboration with the Society of Atherosclerosis Imaging and Prevention and the Society of Cardiovascular Computed Tomography. J Am Coll Cardiol. 2007;49(3):378–402. â•‡ 31. Raggi P, Cooil B, Shaw LJ, et al. Progression of coronary calcium on serial electron beam tomographic scanning is greater in patients with future myocardial infarction. Am J Cardiol. 2003;92(7):827–829. â•‡ 32. Raggi P, Callister TQ, Shaw LJ. Progression of coronary artery calcium and risk of first myocardial infarction in patients receiving cholesterol-lowering therapy. Arterioscler Thromb Vasc Biol. 2004. â•‡ 33. Raggi P, Cooil B, Ratti C, Callister TQ, Budoff M. Progression of coronary artery calcium and occurrence of myocardial infarction in patients with and without diabetes mellitus. Hypertension. 2005;46(1):238–243. â•‡ 34. Arad Y, Spadaro LA, Roth M, Newstein D, Guerci AD. Treatment of asymptomatic adults with elevated coronary calcium scores with atorvastatin, vitamin C, and vitamin E: the St. Francis Heart Study randomized clinical trial. J Am Coll Cardiol. 2005;46(1):166–172. â•‡ 35. Raggi P, Davidson M, Callister TQ, et al. Aggressive versus moderate lipid-lowering therapy in hypercholesterolemic postmenopausal women: Beyond Endorsed Lipid Lowering with EBT Scanning (BELLES). Circulation. 2005;112(4):563–571. â•‡ 36. Taylor AJ, Bindeman J, Bauer K, et al. Does the detection of coronary artery calcium lead to increased use of statin and aspirin in primary prevention? [abstract]. Circulation. 2007;114:II–823. â•‡ 37. Shaw LJ, Raggi P, Berman DS, Callister TQ. Coronary artery calcium as a measure of biologic age. Atherosclerosis. 2006;188(1):112–119. â•‡ 38. Hausleiter J, Meyer T, Hadamitzky M, Kastrati A, Martinoff S, Schomig A. Prevalence of noncalcified coronary plaques by 64-slice computed tomography in patients with an intermediate risk for significant coronary artery disease. J Am Coll Cardiol. 2006;48(2):312–318. â•‡ 39. Knez A, Becker A, Leber A, et al. Relation of coronary calcium scores by electron beam tomography to obstructive disease in 2115 symptomatic patients. Am J Cardiol. 2004;93(9):1150–1152. â•‡ 40. Leber AW, Knez A, von ZF, et al. Quantification of obstructive and nonobstructive coronary lesions by 64-slice computed tomography: a comparative study with quantitative coronary angiography and intravascular ultrasound. J Am Coll Cardiol. 2005;46(1):147–154. â•‡ 41. Leber AW, Knez A, Becker A, et al. Accuracy of multidetector spiral computed tomography in identifying and differentiating the composition of coronary atherosclerotic plaques: a comparative study with intracoronary ultrasound. J Am Coll Cardiol. 2004;43(7): 1241–1247.

314

â•‡ 42. Ehara S, Kobayashi Y, Yoshiyama M, et al. Spotty calcification typifies the culprit plaque in patients with acute myocardial infarction: an intravascular ultrasound study. Circulation. 2004;110(22):3424–3429. â•‡ 43. Zanzonico P, Rothenberg LN, Strauss HW. Radiation exposure of computed tomography and direct intracoronary angiography: risk has its reward. J Am Coll Cardiol. 2006;47(9):1846–1849. â•‡ 44. Onuma Y, Tanabe K, Nakazawa G, et al. Noncardiac findings in cardiac imaging with multidetector computed tomography. J Am Coll Cardiol. 2006;48(2):402–406. â•‡ 45. O’Leary DH, Polak JF, Wolfson SKJ, et al; Use of sonography to evaluate carotid atherosclerosis in the elderly. The Cardiovascular Health Study. CHS Collaborative Research Group. Stroke. 1991;22(9):1155–1163. â•‡ 46. Howard G, Sharrett AR, Heiss G, et al Carotid artery intimalmedial thickness distribution in general populations as evaluated by B-mode ultrasound. ARIC Investigators. Stroke. 1993;24(9): 1297–1304. â•‡ 47. Crouse JR III, Craven TE, Hagaman AP, Bond MG. Association of coronary disease with segment-specific intimal-medial thickening of the extracranial carotid artery. Circulation. 1995;92(5):1141–1147. â•‡ 48. Stensland-Bugge E, Bonaa KH, Joakimsen O. Reproducibility of ultrasonographically determined intima-media thickness is dependent on arterial wall thickness. The Tromso Study. Stroke. 1997;28(10): 1972–1980. â•‡ 49. del Sol AI, Moons KG, Hollander M, et al. Is carotid intima-media thickness useful in cardiovascular disease risk assessment? The Rotterdam Study. Stroke. 2001;32(7):1532–1538. â•‡ 50. Kanters SD, Algra A, van Leeuwen MS, Banga JD. Reproducibility of in vivo carotid intima-media thickness measurements: a review. Stroke. 1997;28(3):665–671. â•‡ 51. Chambless LE, Heiss G, Folsom AR, et al. Association of coronary heart disease incidence with carotid arterial wall thickness and major risk factors: the Atherosclerosis Risk in Communities (ARIC) Study, 1987–1993. Am J Epidemiol. 1997;146(6):483–494. â•‡ 52. O’Leary DH, Polak JF, Kronmal RA, Manolio TA, Burke GL, Wolfson SKJ Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular Health Study Collaborative Research Group. N Engl J Med. 1999;340(1):14–22. â•‡ 53. Urbina EM, Srinivasan SR, Tang R, Bond MG, Kieltyka L, Berenson GS. Impact of multiple coronary risk factors on the intima-media thickness of different segments of carotid artery in healthy young adults (The Bogalusa Heart Study). Am J Cardiol. 2002;90(9):953–958. â•‡ 54. D’Agostino RB Jr, Burke G, O’Leary D, et al. Ethnic differences in carotid wall thickness. The Insulin Resistance Atherosclerosis Study. Stroke. 1996;27(10):1744–1749. â•‡ 55. Davis PH, Dawson JD, Riley WA, Lauer RM. Carotid intimal-medial thickness is related to cardiovascular risk factors measured from childhood through middle age: the Muscatine Study. Circulation. 2001;104(23):2815–2819. â•‡ 56. Raitakari OT, Juonala M, Kahonen M, et al. Cardiovascular risk factors in childhood and carotid artery intima-media thickness in adulthood: the Cardiovascular Risk in Young Finns Study. JAMA. 2003;290(17):2277–2283. â•‡ 57. Tzou WS, Douglas PS, Srinivasan SR, et al. Increased subclinical atherosclerosis in young adults with metabolic syndrome: the Bogalusa Heart Study. J Am Coll Cardiol. 2005;46(3):457–463. â•‡ 58. Burke GL, Evans GW, Riley WA, et al. Arterial wall thickness is associated with prevalent cardiovascular disease in middle-aged adults. The Atherosclerosis Risk in Communities (ARIC) Study. Stroke. 1995;26(3):386–391. â•‡ 59. O’Leary DH, Polak JF, Kronmal RA, et al. Distribution and correlates of sonographically detected carotid artery disease in the Cardiovascular Health Study. The CHS Collaborative Research Group. Stroke. 1992;23(12):1752–1760.

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â•‡ 60. Salonen JT, Salonen R. Ultrasound B-mode imaging in observational studies of atherosclerotic progression. Circulation. 1993;87(3) (suppl):II56–II65. â•‡ 61. Bots ML, Hoes AW, Koudstaal PJ, Hofman A, Grobbee DE. Common carotid intima-media thickness and risk of stroke and myocardial infarction: the Rotterdam Study. Circulation. 1997;96(5):1432–1437. â•‡ 62. O’Leary DH, Polak JF, Kronmal RA, Manolio TA, Burke GL, Wolfson SK Jr. Carotidartery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular Health Study Collaborative Research Group. N Engl J Med. 1999;340(1):14–22. â•‡ 63. Crouse JR III. Predictive value of carotid 2-dimensional ultrasound. Am J Cardiol. 2001;88(2A):27E–30E. â•‡ 64. Cashin-Hemphill L, Mack WJ, Pogoda JM, Sanmarco ME, Azen SP, Blankenhorn DH. Beneficial effects of colestipol-Â� niacin on coronary atherosclerosis. A 4-year follow-up. JAMA. 1990;264(23):3013–3017. â•‡ 65. Hodis HN, Mack WJ, LaBree L, et al. The role of carotid arterial intima-media thickness in predicting clinical coronary events. Ann Intern Med. 1998;128(4):262–269. â•‡ 66. de Groot E, Jukema JW, van Boven AJ, et al. Effect of pravastatin on progression and regression of coronary atherosclerosis and vessel wall changes in carotid and femoral arteries: a report from the Regression Growth Evaluation Statin Study. Am J Cardiol. 1995;76(9):40C–46C. â•‡ 67. Taylor AJ, Sullenberger LE, Lee HJ, Lee JK, Grace KA. Arterial biology for the investigation of the treatment effects of reducing cholesterol (ARBITER) 2: a double-blind, placebo-controlled study of extended-release niacin on atherosclerosis progression in secondary prevention patients treated with statins. Circulation. 2004;110(23):3512–3517. â•‡ 68. Taylor AJ, Lee HJ, Sullenberger LE. The effect of 24 months of combination statin and extended-release niacin on carotid intima-media thickness: ARBITER 3. Curr Med Res Opin. 2006;22(11):2243–2250. â•‡ 69. Taylor AJ, Villines TC, Stanek EJ, et al. Extended-release niacin or ezetimibe and carotid intima-media thickness. N Engl J Med. 2009;361(22):2113–2122. â•‡ 70. Gronholdt ML, Nordestgaard BG, Wiebe BM, Wilhjelm JE, Sillesen H. Echo-lucency of computerized ultrasound images of carotid atherosclerotic plaques are associated with increased levels of triglyceride-rich lipoproteins as well as increased plaque lipid content. Circulation. 1998;97(1):34–40. â•‡ 71. Honda O, Sugiyama S, Kugiyama K, et al. Echolucent carotid plaques predict future coronary events in patients with coronary artery disease. J Am Coll Cardiol. 2004;43(7):1177–1184. â•‡ 72. Tang R, Hennig M, Thomasson B, et al. Baseline reproducibility of B-mode ultrasonic measurement of carotid artery intima-media thickness: the European Lacidipine Study on Atherosclerosis (ELSA). J Hypertens. 2000;18(2):197–201. â•‡ 73. Baldassarre D, Amato M, Pustina L, et al. Measurement of carotid artery intima-media thickness in dyslipidemic patients increases the power of traditional risk factors to predict cardiovascular events. Atherosclerosis. 2007;191(2):403–408. â•‡ 74. Stein JH, Fraizer MC, Aeschlimann SE, Nelson-Worel J, McBride PE, Douglas PS. Vascular age: integrating carotid intima-media thickness measurements with global coronary risk assessment. Clin Cardiol. 2004;27(7):388–392. â•‡ 75. Greenland P, Abrams J, Aurigemma GP, et al. Prevention Conference V: beyond secondary prevention: identifying the high-risk patient for primary prevention: noninvasive tests of atherosclerotic burden: Writing Group III. Circulation. 2000;101(1):E16–E22. â•‡ 76. Fayad ZA, Fuster V. Clinical imaging of the high-risk or vulnerable atherosclerotic plaque. Circ Res. 2001;89(4):305–316. â•‡ 77. Fayad ZA, Fuster V, Nikolaou K, Becker C. Computed tomography and magnetic resonance imaging for noninvasive coronary angiography and plaque imaging: current and potential future concepts. Circulation. 2002;106(15):2026–2034.

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â•‡ 78. Itskovich VV, Samber DD, Mani V, et al. Quantification of human atherosclerotic plaques using spatially enhanced cluster analysis of multicontrast-weighted magnetic resonance images. Magn Reson Med. 2004;52(3):515–523. â•‡ 79. Worthley SG, Helft G, Fuster V, et al. Noninvasive in vivo magnetic resonance imaging of experimental coronary artery lesions in a porcine model. Circulation. 2000;101(25):2956–2961. â•‡ 80. Yuan C, Beach KW, Smith LH Jr, Hatsukami TS. Measurement of atherosclerotic carotid plaque size in vivo using high resolution magnetic resonance imaging. Circulation. 1998;98(24):2666–2671. â•‡ 81. Corti R, Fayad ZA, Fuster V, et al. Effects of lipid-lowering by simvastatin on human atherosclerotic lesions: a longitudinal study by high-resolution, noninvasive magnetic resonance imaging. Circulation. 2001;104(3):249–252. â•‡ 82. Hatsukami TS, Ross R, Polissar NL, Yuan C. Visualization of fibrous cap thickness and rupture in human atherosclerotic carotid plaque in vivo with high-resolution magnetic resonance imaging. Circulation. 2000;102(9):959–964. â•‡ 83. Fayad ZA, Nahar T, Fallon JT, et al. In vivo magnetic resonance evaluation of atherosclerotic plaques in the human thoracic aorta: a comparison with transesophageal echocardiography. Circulation. 2000;101(21):2503–2509. â•‡ 84. Coulden RA, Moss H, Graves MJ, Lomas DJ, Appleton DS, Weissberg PL. High resolution magnetic resonance imaging of atherosclerosis and the response to balloon angioplasty. Heart. 2000;83(2):188–191. â•‡ 85. Jaffer FA, O’Donnell CJ, Larson MG, et al. Age and sex distribution of subclinical aortic atherosclerosis: a magnetic resonance imaging examination of the Framingham Heart Study. Arterioscler Thromb Vasc Biol. 2002;22(5):849–854. â•‡ 86. Yuan C, Kerwin WS, Ferguson MS, et al. Contrast-enhanced high resolution MRI for atherosclerotic carotid artery tissue characterization. J Magn Reson Imaging. 2002;15(1):62–67. â•‡ 87. Sirol M, Fuster V, Fayad ZA. Plaque imaging and characterization using magnetic resonance imaging: towards molecular assessment. Curr Mol Med. 2006;6(5):541–548. â•‡ 88. Kim WY, Danias PG, Stuber M, et al. Coronary magnetic resonance angiography for the detection of coronary stenoses. N Engl J Med. 2001;345(26):1863–1869. â•‡ 89. Corti R, Fayad ZA, Fuster V, et al. Effects of lipid-lowering by simvastatin on human atherosclerotic lesions: a longitudinal study by high-resolution, noninvasive magnetic resonance imaging. Circulation. 2001;104(3):249–252. â•‡ 90. Corretti MC, Anderson TJ, Benjamin EJ, et al. Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force. J Am Coll Cardiol. 2002;39(2):257–265. â•‡ 91. Celermajer DS, Sorensen KE, Georgakopoulos D, et al. Cigarette smoking is associated with dose-related and potentially reversible impairment of endothelium-dependent dilation in healthy young adults. Circulation. 1993;88(5, pt 1):2149–2155. â•‡ 92. Harris CW, Edwards JL, Baruch A, et al. Effects of mental stress on brachial artery flow-mediated vasodilation in healthy normal individuals. Am Heart J. 2000;139(3):405–411. â•‡ 93. Vogel RA. Coronary risk factors, endothelial function, and atherosclerosis: a review. Clin Cardiol. 1997;20(5):426–432. â•‡ 94. Herrington DM, Fan L, Drum M, et al. Brachial flow-mediated vasodilator responses in population-based research: methods, reproducibility and effects of age, gender and baseline diameter. J Cardiovasc Risk. 2001;8(5):319–328.

315

â•‡ 95. Cai H, Harrison DG. Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress. Circ Res. 2000;87(10):840–844. â•‡ 96. Bonetti PO, Lerman LO, Lerman A. Endothelial dysfunction: a marker of atherosclerotic risk. Arterioscler Thromb Vasc Biol. 2003;23(2):168–175. â•‡ 97. Vita JA, Treasure CB, Nabel EG, et al. Coronary vasomotor response to acetylcholine relates to risk factors for coronary artery disease. Circulation. 1990;81(2):491–497. â•‡ 98. Schachinger V, Britten MB, Zeiher AM. Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Circulation. 2000;101(16):1899–1906. â•‡ 99. Gokce N, Keaney JF Jr, Hunter LM, Watkins MT, Menzoian JO, Vita JA. Risk stratification for postoperative cardiovascular events via noninvasive assessment of endothelial function: a prospective study. Circulation. 2002;105(13):1567–1572. 100. Chan SY, Mancini GB, Kuramoto L, Schulzer M, Frohlich J, Ignaszewski A. The prognostic importance of endothelial dysfunction and carotid atheroma burden in patients with coronary artery disease. J Am Coll Cardiol. 2003;42(6):1037–1043. 101. Mancini GB. Vascular structure versus function: is endothelial dysfunction of independent prognostic importance or not? J Am Coll Cardiol. 2004;43(4):624–628. 102. Anderson TJ. Assessment and treatment of endothelial dysfunction in humans. J Am Coll Cardiol. 1999;34(3):631–638. 103. Rupard EJ, O’Malley PG, Jones DL, Feuerstein IM, Brazaitis M, Taylor AJ. Knowledge of preclinical coronary artery disease: the effect on motivation to change smoking behavior. West J Med. In press. 104. Wong ND, Detrano RC, Diamond G, et al. Does coronary artery screening by electron beam computed tomography motivate potentially beneficial lifestyle behaviors? Am J Cardiol. 1996;78(11):1220–1223. 105. Shahab L, Hall S, Marteau T. Showing smokers with vascular Â�disease images of their arteries to motivate cessation: a pilot study. Br J Health Psychol. 2007;12(pt 2):275–283. 106. Bovet P, Perret F, Cornuz J, Quilindo J, Paccaud F. Improved smoking cessation in smokers given ultrasound photographs of their own atherosclerotic plaques. Prev Med. 2002;34(2):215–220. 107. Bize R, Burnand B, Mueller Y, Cornuz J. Biomedical risk assessment as an aid for smoking cessation. Cochrane Database Syst Rev. 2005;(4):CD004705. 108. O’Malley PG, Feuerstein IM, Taylor AJ. Impact of electron beam tomography, with or without case management, on motivation, behavioral change, and cardiovascular risk profile: a randomized controlled trial. JAMA. 2003;289(17):2215–2223. 109. Lederman J, Ballard J, Njike VY, Margolies L, Katz DL. Information given to postmenopausal women on coronary computed tomography may influence cardiac risk reduction efforts. J Clin Epidemiol. 2007;60(4):389–396. 110. O’Malley PG, Kowalczyk C, Bindeman J, Taylor AJ. A randomized trial assessing the impact of cardiovascular risk factor case-management on the metabolic syndrome. J Cardiometab Syndr. 2006;1(1):6–12. 111. Vale MJ, Jelinek MV, Best JD, et al. Coaching patients On Achieving Cardiovascular Health (COACH): a multicenter randomized trial in patients with coronary heart disease. Arch Int ern Med. 2003;163(22): 2775–2783. 112. Kathiresan S, Larson MG, Keyes MJ, et al. Assessment by Â�cardiovascular magnetic resonance, electron beam computed tomography, and carotid ultrasonography of the distribution of subclinical atherosclerosis across Framingham risk strata. Am J Cardiol. 2007;99(3):310–314.

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Cardiac Masses

VICTOR A. FERRa RI

Cardiac Computed Tomography

AR I D. GOL d BERg

Cross-sectional imaging techniques such as CCT and CMR provide a larger field of view and greater depiction of the cardiopulmonary anatomy than echocardiography. Both techniques provide greater visualization of the paracardiac space and can detect invasion of the pericardium by an adjacent tumor. Conventional helical CT without electrocardiogram (ECG) gating can identify masses and pericardial effusions, but less accurately than newer 64-detector (or greater) ECG-gated CCT machines. Current scanners permit submillimeter isotropic voxel image resolution, enabling multiplanar reconstructions along any axis. Dynamic cine imaging using CCT is now available to assess mass mobility, but at a lower temporal resolution than echo or CMR. CCT has improved tissue characterization capabilities over echo, such that fat and calcification are easily identified. The relative densities of masses may be measured using Hounsfield units, which may provide additional clues as to their etiology, particularly fat-containing structures. In fact, CCT is the best technique for detection of calcification of the major modalities due to calcium’s high density. Following IV contrast administration, the enhancement of cardiac masses relative to normal myocardium may be assessed. Delayed enhancement CT techniques for detection of fibrosis have been developed for ischemic heart disease, but are in evolution for cardiac masses and other applications. A major limitation of CCT is the need for ionizing radiation, which in the ECG-gated multislice mode, commonly exceeds the exposure of a cardiac catheterization. Another drawback is the requirement for intravenous iodinated contrast material, which may result in nephrotoxicity or allergic reactions. Occasionally, mixing of contrast with unopacified blood at the superior vena cava–right atrial junction may limit detection of lesions in this area.

jâ•… INTRODUCTION Cardiac masses may represent a spectrum of disorders from normal intracardiac structures to malignant processes. The primary goal of noninvasive cardiac testing is to distinguish benign conditions from malignant diseases in order to direct appropriate patient management. Multimodality imaging tools of choice for evaluating cardiac masses include echocardiography, cardiac magnetic resonance (CMR), cardiac computed tomography (CCT), and on occasion, nuclear imaging. The majority of patients with cardiac masses will come to attention following one of the studies above, most commonly an echocardiogram. The following paragraphs will describe these techniques and their advantages and limitations. Echocardiography The initial imaging technique used most commonly in the diagnosis of cardiac disorders is transthoracic echocardiography (TTE). The many advantages of TTE include its widespread availability, portability, relatively low cost, ease of operation, and lack of ionizing radiation or need for contrast agents. The technique is useful for delineating the general size, location, and extent of cardiac masses, but may be rendered nondiagnostic by limited acoustic windows due to chest wall deformities and abnormal body habitus, or disorders such as chronic obstructive pulmonary disease. An additional shortcoming is the technique’s inability to further characterize soft tissue masses beyond the descriptions above. Transesophageal echocardiography (TEE) eliminates most problems related to unfavorable acoustic windows but has a smaller field of view and requires conscious sedation and esophageal intubation without optical guidance. TEE also suffers from the same limitations as TTE regarding greater tissue characterization of masses.

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Cardiac Magnetic Resonance CMR is the most robust of the noninvasive imaging technique for cardiac masses. It provides a large field of view, multiplanar imaging along any axis, and high temporal

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and spatial resolution. Its tissue characterization capabilities are outstanding, even without intravenous contrast material, and CMR is the best of the noninvasive imaging techniques in this regard. There are no problems related to acoustic windows, and no ionizing radiation or iodinated contrast material is used. First-pass perfusion and delayed contrast enhancement techniques are very useful to determine the vascularity of tumors, as well as the degree of fibrous tissue present. However, due to concerns related to nephrogenic systemic fibrosis, MRI contrast agents should not be given to patients whose GFR is less than 30 mL/min and used only with great caution in those with a GFR less than 60 mL/min. Tissue tagging techniques can also depict intramyocardial borders of tumors based on contractile function, or assist in assessing tumor invasion of structures. Some disadvantages of CMR include its limited availability, lack of portability, greater complexity when scanning critically ill patients, exclusion of patients with certain cerebral aneurysm clips, and special precautions when scanning patients with permanent pacemakers or internal cardiac defibrillators. In addition, calcium and calcifications are more difficult to detect on CMR, frequently requiring cross-correlation with CT or plain X-ray films. A list of the imaging characteristics of cardiac masses by benign and malignant etiology is shown in Table 20.1A and Table 20.1B, and a guide for determining the likelihood of tumor type by affected chamber is presented in Table 20.2.

j â•… BENIGN CARDIAC MASSES Primary cardiac tumors are a rare disorder and have an incidence of between 0.002% and 0.19% in an autopsy series [1]. Benign tumors account for 75% of this total, while 25% are malignant. Myxomas are the most common benign cardiac tumor, comprising over 50% of this category in adults [2]. In general, 75% of myxomas are located in the left atrium, less than 25% are found in the right atrium, and only 2% in the left ventricle [3–6]. Other benign tumors (in order of frequency) include lipomas (16%), papillary fibroelastomas (16%), hemangiomas (6%), fibromas (3%), and rhabdomyomas (1%). Rarer benign tumors include neurofibromas, teratomas, and paragangliomas (a neuroendocrine tumor) [7]. Myxomas The most common attachment site for myxomas is at the fossa ovalis of the interatrial septum, frequently on a thin stalk, though attachment sites can be quite broad in some tumors. Common presenting symptoms include dyspnea due to left ventricular inflow tract obstruction by an enlarging tumor, or the myxoma syndrome consisting of fever of unknown origin, fatigue, weight loss, elevated

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erythrocyte sedimentation rate, and occasionally systemic embolism [3,6]. The latter is more commonly associated with left atrial myxomas. Patients with large right atrial myxomas can present with right heart failure symptoms. A rare autosomal dominant disorder known as Carney syndrome includes multicentric myxomas, cutaneous spotty pigmentation, and endocrine disorders. Two-thirds of these patients have cardiac myxomas, which have a propensity to regrow after surgical excision [8]. The tumors tend to be round or oval shaped, occasionally with villous Â�attachments covered with thrombus in various states of organization. Within the tumor are areas of fibrosis, calcification, erratic vasculature with hemorrhage, and polysaccharide-rich myxoid tissue.

Imaging Characteristics Echocardiography can readily identify atrial myxomas in their typical locations along the right and left interatrial septum. The stalks or bases of the tumors are easily seen, and their characteristic motion patterns (movement toward the valve plane during diastole) are well depicted. This is especially true of TEE, since the probe is located immediately posterior to the left atrium, and the verrucous components of the mass which prolapse toward or across the mitral valve are well seen (Figure 20.1). The impact of the masses on mitral valve function, with resultant stenosis or regurgitation, can be assessed with Doppler techniques [9]. Difficulties arise with echo when attempting to identify myxomas that occur in atypical locations, due to limited tissue characterization capabilities. Myxomas are identifiable on CT as well-defined spherical or oval masses with a heterogeneous density pattern (due to myxoid material or ground substance), and typically have areas of calcification [10]. On CMR, myxomas often have variable signal intensity based on their components. The calcified and fibrous components demonstrate low T1 and T2 signal intensity compared to myocardium, the polysaccharide-rich myxoid areas have low signal on T1-weighted sequences but high T2 signal, and hemorrhagic areas have variable signal intensity based on the age of hemorrhage and the hemoglobin breakdown state [11]. Acute hemorrhage demonstrates a low to intermediate signal intensity on T1-weighted sequences and low signal intensity on T2-weighted sequences. Subacute hemorrhage has a high T1 and T2 signal intensity, and many myxomas have low signal intensity on T2*-weighted gradient echo images, likely due to susceptibility artifacts related to iron Â�deposition from hemoglobin breakdown products. Following gadolinium contrast administration, heterogeneous enhancement occurs with little enhancement in the calcific and myxoid regions, but with significant enhancement corresponding to areas of inflammation [12]. Differentiating myxomas from thrombus with CMR may sometimes be challenging since both may contain

jâ•… Table 20.1Aâ•… Benign Masses Mass Type (in order of frequency)

Location

Imaging Features by:

Associated Clinical Features

Echocardiography

CCT

CMR

Benign tumors/ masses* Younger adults Carney complex

Myxoma

In left atrium in the majority of cases Attachment to the interatrial septum via small stalk

Round or oval-shaped, gelatinous appearance Homogeneous or heterogeneous echogenicity, occasionally calcifications Frequently highly mobile

Low attenuation Calcifications may be seen Heterogeneous or homogeneous density and Enh pattern

T1W: Iso, Hetero T2W: Hyper, Hetero Cine: Hyper Enh: Homo or hetero DE: Hetero

Lipoma

Subendo or subepicardial LV, RV, interatrial septum

Echodense (when intramural or intracavitary) Echolucent (when intrapericardial) Low mobility

Low attenuation (fat density) Homogeneous NonEnh

T1W: Hyper, homogeneous Can occur at any age, Displaces tissues and T2W: Hyper structures, does not invade Cine: Hyper NonEnh DE: None FS: Marked hypo

Papillary fibroelastoma

Valves or subvalvular apparatus “Sea-anemone” or shimmering/frondlike appearance

Highly mobile, usually , 1 cm Shimmering Attached via stalk

Hard to visualize Low attenuation NonEnh

Difficult to visualize T1W: Iso T2W: Iso

Typically very small and highly mobile lesions difficult to visualize with CCT and CMR

Fibroma

Usually single tumor Intramural in LV, occasionally intrapericardial Frequently calcified

Echodense Scattered calcifications

Low attenuation, numerous calcifications Enh: Homo- or heterogeneous

T1W: Iso or Hyper, homogeneous T2W: Hypo Cine: Iso Enh: Hypo DE: Hyper (marked)

Infants to young adults Gorlin syndrome

Hemangioma

Intramural (RV or LV), RA, Echodense with multiple intrapericardial echo-free areas (“Spongy” architecture) Occasional calcifications

Heterogeneous, calcifications Enh: Dramatic

T1W: Hyper, hetero T2W: Hyper, hetero Cine: Hyper Enh: Hyper DE: Hyper (marked)

Any age

Paraganglioma

Atrial walls (usually LA), aortic root

Iso or low attenuation, with central necrosis common Enh: Dramatic

T1W: Iso, hypo T2W: Hyper Enh: Hyper (marked) DE: Hyper (marked)

Young adults

Echodense, sessile Typically in dome of LA

Benign masses that mimic tumors Acute/subacute thrombus

LAA in Afib, LA in MS, LV apex post-MI (or in CHF), RA in CHF or post OHT

Acute: Gelatinous-appearing, single or multiple masses

Low attenuation, usually attached to chamber wall NonEnh: Homogeneous filling defect

Acute thrombi: Homogeneous T1W: Hyper T2W: Hyper NonEnh DE: None Subacute: T1W: Hyper T2W: Hyper, hetero NonEnh DE: None

Subacute thrombus is hyperintense on T2W, but has a hetero pattern due to areas of methemoblobin

Chronic thrombus

(same as above)

Echodense, single or multiple masses

Chronic thrombi may be calcified NonEnh: Homogeneous filling defect

T1W: Hypo T2W: Hypo NonEnh DE: None

Occasionally, minimal surface enhancement is seen in chronic thrombi due to neovascularization

Lipomatous hypertrophy of the interatrial septum

Interatrial septum, upper right atrium

Echodense, spares fossa ovalis

Low attenuation (fat density) Enh: Iso to hypo

T1W: Hyper T2W: Mild hypo Enh: Iso DE: None FS: Marked hypo

Fat can extend to the distal superior vena cava

Pericardial cyst

Pericardium

Fluid density, circumferential or circumscribed fluid-filled mass

Low attenuation (water density) collection within pericardium

T1W: Hypo T2W: Hyper NonEnh DE: None

May be very large and cause chamber compression or tamponade physiology

Postoperative inflammatory changes

Paracardiac

Echodense mass adjacent to cardiac structures

T1W: Iso with hetero Tissue density Enh: Variable enhancement T2W: Iso with hetero Enh: Iso characteristics depending on age

Chronicity will determine signal properties and enhancement. Resolves with time

Table 20.1Bâ•… Malignant Tumors Mass Type (in order of frequency)

Location

Imaging Features by:

Associated Clinical Features

Echocardiography

CCT

CMR

Malignant tumors Metastatic disease

Variable pattern and chamber involvement depending on primary tumor and stage

Pericardial effusions and masses are common, tissue invasion by masses common

Usually isoattenuating, good depiction of pericardial involvement. Enh: Iso

Variable, but commonly: T1W: Hypo T2W: Iso Enh: Hetero (depending on degree of necrosis)

Melanoma is a special case: Hyper on T1W, Hyper on T2W

Angiosarcoma

RA, broad-based, can infiltrate pericardium Invasive, heterogeneous with necrosis

Echodense, invasive into adjacent structures Heterogeneous, pericardial effusion common

Low attenuation with hetero reflecting necrosis Enh: Hetero Pericardial effusion

T1W: Iso with focal hyper T2W: Iso, hetero Cine: Hetero, some hyper Enh: Prominent DE: Linear, hetero in “sunray” pattern

Adults, can present with tamponade. T1W pattern due to necrosis, known as “cauliflower” appearance

Osteosarcoma

Posterior LA, broad-based, Invasive

Echodense, heteroÂ�geÂ�neous mass Calcification commonly seen

Increased attenuation: Frequently heavily calcified Enh: Hetero

T1W: Iso, hetero T2W: Hyper, hetero Cine: Iso, hetero Enh: Prominent, hetero DE: Hetero, Nonspecific

Frequently arises from mitral valve, pulmonary venous obstruction common

Lymphoma

RA and RV most frequent, effusions common

Echolucent, broad-based, remote from interatrial septum, invasive, effusion. Hypokinesis comÂ�mon when intramural

Low or iso-attenuating Enh: Hetero

T1W: Iso to hypo T2W: Iso to hyper Enh: Intense, hetero DE: Hetero

Tagging may assist in evaluating regional hypokinesis

Pericardial mesothelioma

Pericardial effusion and intrapericardial mass

Intrapericardial mass with pericardial effusion, often large

Isoattenuating, but can be variable

T1W: Variable pattern T2W: Variable pattern Enh: Hetero

Legend: T1W – T1-weighted, T2W – T2-weighted, Cine – Cine (Steady state free precession) imaging, Enh – Enhances post-contrast, NonEnh – No enhancement post-contrast, DE – Delayed enhancement imaging, FS – Fat saturation. RA – Right atrium, LA – Left atrium, LV – Left ventricle, RV – Right ventricle, LAA – Left atrial appendage, Afib – Atrial fibrillation, MI – Myocardial infarction, CHF – Congestive heart failure, OHT – Orthotopic heart transplantation Tumor signal intensity relative to myocardial tissue signal intensity: Iso – Isointense, Hypo – Hypointense, Hyper – Hyperintense, Hetero – Heterogeneous. * 5 Note that rhabdomyomas and rhabdomyosarcomas are predominantly pediatric disorders and will not be formally reviewed. The citations referenced discuss these tumors in detail.

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Table 20.2â•… Likelihood of Tumor Type by Chamber Involvement Chamber

Mass/Tumor Type*

RA

Angiosarcoma, myxoma, thrombus, metastatic disease, paraganglioma, lymphoma, other sarcomas

RV and LV

Fibroma, lipoma – Often single and encapsulated-appearing. Thrombus, hemangioma, metastatic disease, myxoma, sarcoma, lymphoma, rhabdomyoma

Interatrial septum

Lipomatous hypertrophy, lipoma, metastatic disease

LA, including appendage

Myxoma, thrombus, osteosarcoma, paraganglioma, other sarcomas

Valves

Fibroelastoma, osteosarcoma, thrombus, fibroma, rhabdomyosarcoma, fibrosarcoma

Pericardium

Lipoma, metastatic disease, mesothelioma, pericardial cyst, hemangioma

Legend: RA – Right atrium, LA – Left atrium, RV – Right ventricle, LV – Left ventricle * 5 Note that metastatic tumor can affect any chamber by direct extension or hematogenous spread.

A

B

C

D

F igure 2 0 . 1 â•… (A) Left atrial myxoma—transesophageal echocardiogram (TEE) in the mid-esophageal 4-chamber view demonstrates a large, lobu-

lated mass attached via a narrow base to the left side of the interatrial septum (IAS). The findings are most compatible with an atrial myxoma (arrow). (B) In diastole, the tumor is seen to prolapse across the mitral valve plane (arrowheads) and partially obstruct mitral inflow. Dynamic imaging of mass motion with TEE permits depiction of narrow base of attachment of mass to the IAS (between arrows). Of note, this patient had a remote history of malignant melanoma, but preoperative TEE and cardiac magnetic resonance (CMR) predicted a myxoma, and showed no characteristic findings of melanoma within the tumor. A myxoma was confirmed at pathology. RA, right atrium; RV, right ventricle; LA, left atrium; LV, left ventricle. (C) Axial plane enhanced cardiac computed tomography (CCT) demonstrates a lobulated, hypoenhancing and attenuating mass attached to the left side of the interatrial septum consistent with a left atrial myxoma (arrow). The location and appearance enable prompt diagnosis by CMR as well. In contrast to echocardiography, greater characterization of the tissue composition and density is achievable with CCT and CMR. (D) Right ventricular myxoma— sagittal plane, post-contrast, T1-weighted (T1W) image showing a lobulated, heterogeneously enhancing mass (M) prolapsing across the pulmonary valve (PV, middle arrow) during systole. The signal characteristics and location of the mass are characteristic of a right ventricular myxoma. Contrast between the blood pool and a nonstationary mass, especially with valvular involvement, is a strength of cardiac magnetic resonance. Important sequences include balanced steady-state free precession cine and post-contrast T1W, as shown here.

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calcifications. However, thrombi tend to be located more posteriorly or along the dome of the atrium and typically will not enhance following contrast delivery. Occasionally, some peripheral enhancement may occur in chronic organized thrombi due to surface neovascularization. Lipomas Lipomas are composed of mature adipose cells and can occur in children or adults. They usually occur as single lesions within the pericardium, but may present as an intramyocardial mass or develop along the endocardial surface. Most patients are asymptomatic, but intracavitary masses may cause dyspnea, and intramyocardial lipomas may cause arrhythmias.

Imaging Characteristics The echocardiographic appearance of lipomas is dependent on their location. While intramyocardial and intracavitary lipomas appear homogenous and hyperechoic, intrapericardial lipomas may be hypoechoic or hyperechoic [13] (Figure 20.2). CT demonstrates homogenous low-density tissue within the lipoma, but fibrous tissue and stranding with higher attenuation characteristics may be present within the lesion [14]. Lipomas typically have a high T1 signal and a slightly lower T2 signal, comparable to subcutaneous fat. A characteristic feature of lipomas is a marked reduction in signal intensity when a fat saturation sequence is applied [14,15]. Frequently, a hypointense signal is seen along the border of the mass with balanced steady-state free precession sequences due to susceptibility artifacts. Occasionally, large lipomas may be seen on cardiac SPECT imaging as well [16]. Papillary Fibroelastomas Papillary fibroelastomas are usually small tumors found on the valvular or endocardial surface of older patients. Most patients are asymptomatic, although embolic phenomena or rare instances of sudden death related to coronary ostial obstruction are known to occur. The tumors attach to the valves or endocardial surfaces of the heart by a stalk and have multiple armlike fronds emanating from a central structure, often compared to those of a sea anemone [17].

Imaging Characteristics Echocardiography demonstrates a homogeneous pedunculated mass that has a characteristic mobility with fluttering or shimmering of the tumor fronds with valvular or blood motion [18,19]. The lesions are difficult to visualize with CCT due to their small size and rapid motion. However, larger lesions are detectable at times, and also have a similar motion pattern on cine imaging (Figure 20.3). CMR cine imaging usually identifies the masses well when they

F igure 2 0 . 2 â•… Septal lipoma. (Top) Transthoracic echocardiogram

in the apical 4-chamber view demonstrating a hyperechoic, well-Â� circumscribed mass in the interventricular septum (arrow). Axial plane enhanced cardiac computed tomography (CCT) image (Bottom) of the same patient shows a nonenhancing, fat density (low Hounsfield units) lesion in the interventricular septum (arrow). Such a lesion could be equally well characterized on cardiac magnetic resonance, but the density and enhancement characteristics on CCT are diagnostic.

are greater than 1 cm. On T1- and T2-weighted sequences, the lesions may appear Â�hypointense [19,20]. Fibromas Cardiac fibromas are generally a disease of children, but up to 15% of these tumors may develop in adults. A greater incidence of fibromas is seen in the Gorlin syndrome. As the lesions grow, cardiovascular disorders such as arrhythmias, sudden death, or heart failure may occur. Most lesions

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marked hyperenhancement due to the high Â�proportion of fibrous tissue [23] (Figure 20.4). Paragangliomas

A

Cardiac paragangliomas are very rare tumors that originate from cardiac paraganglial cells located most commonly in the atria. The disorder affects mostly adults, with presenting symptoms similar to those of pheochromocytomas. The tumors produce catecholamines, which cause systemic hypertension, flushing, palpitations, and headache. Serum and urinary catecholamine levels are the laboratory tests most commonly used to confirm the diagnosis. Up to 25% of patients with cardiac paragangliomas may have tumors in other parts of the body. The tumors are generally located on the epicardial surface in the roof of the left atrium. They also may occur within the cavity, in the interatrial septum, and occasionally in the ventricles. Suspicion for cardiac paragangliomas generally arises after an adrenal pheochromocytoma cannot be located in patients with typical symptoms.

Imaging Characteristics

B F igure 2 0 . 3 â•… Papillary fibroelastoma. (A) Coronal plane enhanced cardiac computed tomography image demonstrates a nonenhancing, frondlike lesion of the aortic valve (arrow). The left ventricle (LV) is identified, and the arrow overlies the ascending aorta. (B) Short-axis image of the aortic valve demonstrating the multilobulated morphology of this papillary fibroelastoma. On cine imaging, the mass had an undulating movement pattern typical of this benign tumor.

develop intramyocardially and distort Â�cardiac architecture frequently, entering the ventricular cavities, but are not associated with embolic phenomena [21]. The lesions are homogenous and often have associated calcifications.

Imaging Characteristics On echocardiography, wall motion abnormalities are frequently seen in the territory of the tumors. The masses are usually hypoechoic, but may have variable signal properties due to intratumor calcifications [13]. On CT, fibromas appear as heterogeneous intramural masses and when present, tumor calcifications are well seen [22]. Fibromas generally have homogenous enhancement on contrast sequences, but may be heterogeneous as well. CMR has excellent soft tissue depiction capabilities and shows the intramural heterogeneous masses very well. Fibromas exhibit the typical features of fibrous tissue: on T1-weighted imaging, they have either similar or greater signal intensity than myocardium and have reduced signal intensity on T2-weighted images. On first-pass Â�perfusion imaging, fibromas are usually hypointense due to their low vascularity, but delayed enhancement sequences show

Paragangliomas located in the dome of the left atrium may first come to medical attention on plain film X-ray images. Findings resemble a mid-mediastinal mass with distortion of the carina, or an appearance of left atrial enlargement. On echocardiography, paragangliomas are usually found in the atria, and appear as echodense round or oval masses. Occasionally, a mediastinal or extracardiac paraganglioma may be discovered by TTE or TEE, but these lesions are usually best depicted by CCT or CMR. Occult or metastatic tumors are commonly detected using nuclear imaging with iodine 131 metaiodobenzylguanidine (131I-MIBG) scintigraphy. This technique exploits the characteristically avid tracer uptake by the catecholamine-producing tumor cells. 131I-MIBG scans can be used to detect primary or metastatic lesions with a sensitivity approaching 90% [24,25]. Paragangliomas are isointense compared with surrounding soft tissues on baseline CT scans, but then markedly enhance following iodinated contrast injection. An important point to remember prior to contrast administration is that pretreatment with alpha- and beta-blockers must be performed to avoid hypertensive crises. Over half of the lesions contain central areas of low attenuation representing necrosis. Tumor calcification may also be seen. CMR imaging shows the lesions to be isointense or hypointense on T1-weighted images, and hyperintense on T2-weighted scans. There is prominent first-pass contrast enhancement of the lesions due to the significant vascularity of the tumors [26]. Hemangiomas Hemangiomas are uncommon, benign, and highly Â�vascular tumors that frequently present in the lateral left ventricular wall, the right ventricle, and the Â�interventricular Â�septum.

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A

B

C

D

F igure 2 0 . 4 â•…Intrapericardial fibroma

(A, arrow) with signal properties similar to fibrous tissue. Heterogeneous signal characteristics on axial double-inversion recovery steady-state free precession cardiac magnetic resonance images are seen in panel A. On short-axis balanced steady-state free precession images (B) the tumor (arrow) has isointense to hypointense signal properties relative to myocardium. The tumor is hypointense on first-pass contrast imaging (C) indicative of the relatively low vascularity of the lesion, but has very intense signal properties on delayed enhancement images (D) consistent with the large proportion of fibrous tissue in the mass.

They can appear either intramurally or Â�endocardially based. Patients may present with arrhythmias, Â�shortness of breath, or pericardial effusions—occasionally hemorrhagic.

Imaging Characteristics On echocardiography, hemangiomas appear as inhomogeneous, echodense masses with multiple echo-free areas, giving the tumors a spongy architecture. They also may appear as a single, loculated cystic-appearing intramural, endocardial, or pericardial lesion, or as a solid, echodense lesion. Due to its vascular nature, calcifications are not uncommon, and when associated with the spongiform appearance, are highly suspicious for hemangioma. These tumors are well known for their vascularity and coronary arterial supply with a characteristic tumor blush on coronary angiography. CT typically shows a heterogeneous mass that is isointense with the surrounding myocardium, but which characteristically enhances dramatically with contrast injection. CMR demonstrates a heterogeneous mass with areas of increased signal intensity on T1- and T2-weighted images due to slow blood flow within the highly vascular tumor. Prominent contrast enhancement on first-pass imaging is seen due to the great degree of vascularity.

jâ•… MALIGNANT CARDIAC MASSES While only 25% of all cardiac tumors are malignant, approximately 95% of all malignant tumors are sarcomas. Sarcomas are thus the next most common primary cardiac tumor to myxomas. The other 5% of the primary malignant tumor group are generally lymphomas. Sarcomas The most common cardiac primary tumors are Â�angiosarcomas (30%) and undifferentiated sarcomas (10%–15%), rhabdomyosarcomas (10%), fibrosarcomas (5%–10%), Â�leiomyosarcomas (5%–10%), and osteosarcomas Â�(5%–10%). Other primary cardiac sarcomas have been described, but are exceedingly rare, including Â�liposarcomas, synovial sarcomas, and leiomyosarcomas [2,3]. Some pathologists feel that tumors given the general designation of malignant fibrous histiocytoma are often reclassified following additional staining and examination. Most sarcomas occur in 30- to 60-year-old patients, and symptoms depend on the location of the mass or masses, and their degree of invasiveness. Patients may present with congestive heart failure symptoms, chest pain, and

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pericardial effusion or cardiac tamponade, arrhythmias, or vena caval obstruction. Unfortunately, the majority of malignant cardiac tumors are rapidly growing and associated with brief survival durations following diagnosis. As many as 75% of patients will have metastatic disease to the lung, local lymph nodes, bones, and other structures at the time of death.

Angiosarcomas Angiosarcomas most commonly affect the right atrium, while the other tumors have a predilection for the left atrium. Two patterns of presentations have been observed clinically. The first is that of a wide-based, lobulated right atrial mass, usually along the lateral portion of the atrium, and sparing the interatrial septum. The second is that of an aggressive infiltrating tumor of the right atrial wall with extension into the pericardial space. Nearly half of the patients with angiosarcomas have pericardial effusions, which are frequently hemorrhagic. When the tumors present with intramural involvement, they commonly cause arrhythmias, conduction abnormalities, and sudden death [28,29]. The invasiveness of the tumors distinguishes them from benign lesions—the malignancies do not respect tissue planes, and cross borders of normal cardiac structures to involve the pericardial space, chamber cavities, and other territories. Due to the right-sided location and invasiveness of the tumors, symptoms are usually minor in the early to mid-stages of the disease, and the majority of angiosarcomas have metastases at the time of presentation.

Imaging Characteristics Echocardiography generally demonstrates an invasive right atrial tumor with a pericardial effusion. The tumor commonly extends toward the right ventricle or inferior vena cava. Due to its involvement of the atrial wall, pericardium, and surrounding structures, CCT and CMR are often better at depicting the extent of the tumor, while TTE is best at follow-up imaging after treatment. CCT usually

2 0 . 5 â•… Angiosarcoma—axial (left panel) and short-axis (right panel) balanced steadystate free precession cardiac magnetic resonance (CMR) images demonstrating a hypoenhancing, low–signal intensity mass invading the inferior basal myocardium (arrows). The mass was proven to be a high-grade angiosarcoma on pathology. The myocardial and cavitary involvement are most easily appreciated via black-blood and brightblood sequences, as well as the post-contrast CMR sequences. Tissue invasion is a common feature of malignant tumors, while enhancement characteristics are variable. F igure

32 5

demonstrates a hypointense, heterogeneous, and nodularappearing mass in the right atrium associated with a pericardial effusion, or obliteration of the pericardial space by tumor invasion. Following contrast, angiosarcomas appear as heterogeneously enhancing atrial filling defects with a broad base. Malignant properties of the tumor are suggested by pericardial, inferior vena cava (IVC), and even mediastinal extension. CMR imaging demonstrates heterogeneous T1 and T2 signal intensity profile, with areas of increased signal representing areas of hemorrhage within the tumor, often described as cauliflower-like pattern [30] (Figure 20.5). After contrast, the tumor has a heterogeneous enhancement pattern with regions of prominent enhancement interspersed with areas of lower signal intensity, indicative of tumor necrosis or hemorrhage. Extension of the tumor along the pericardium or within the myocardium may cause enhancement in various patterns, often with a nodular appearance. As with most sarcomas, there is a variable pattern of enhancement on delayed enhancement imaging.

Other Sarcomas Most sarcomas have similar appearances and imaging features to angiosarcomas, with several unique features. Rhabdomyosarcomas are the most common cardiac tumor of infants and children, but can occur in adults as well. While they are the most likely sarcomas to arise from the valves, they most commonly present as multiple, infiltrating myocardial tumors with chamber invasion. They exhibit the broad-based character of many malignancies and frequently invade the pericardium with an associated pericardial effusion. Fibrosarcomas also have a predilection for valvular involvement and frequently present as multiple broad-based tumors, similar to Â�rhabdomyosarcomas. The most distinctive of the sarcomas is the osteosarcomas, which frequently arise from the left atrial wall and are frequently mistaken for benign myxomas. However, the location of the tumor is remote from the interatrial septum, and its extension into the pulmonary veins aids

32 6

in its proper identification as a malignant tumor. As their name suggests, the masses often have prominent calcifications that further distinguish the lesions from other sarcomas. TTE (and more often TEE) can identify these calcifications, and the Â�broad-based Â�nonseptal location of the tumors, as well as the low tumor mobility over the cardiac cycle. CCT is the best of the imaging Â�modalities at detecting the intratumor calcifications, as well as depicting the broad-based nonseptal tumor attachment. CMR features include T1-weighted images that show a heterogeneous intermediate signal intensity, and generally high signal intensity on T2-weighted imaging. On first-pass contrast imaging, there is prominent, but heterogeneous, tumor enhancement. The tumor extension to the pericardium and pulmonary veins is also well depicted by CMR. Lymphomas Primary cardiac lymphomas are rare disorders and make up approximately 5% of all malignancies of the heart. In immunocompromised patients such as those with AIDS, organ transplant recipients on immunosuppressive drug regimens, or other similar conditions, concern for lymphoma is increased when cardiac symptoms develop, and the disease can occur at nearly any age. In patients with normal immune systems however, the median age of detection is in the sixth decade, with males having 3 times the risk of the disease than females [31]. The most common sites of involvement are the right atrium and right ventricle, the left heart chambers, the interatrial septum, and then the interventricular septum. Usually, multiple cardiac chambers are involved, and pericardial invasion and pericardial effusions (often massive, with or without tamponade) commonly occur.

Imaging Characteristics The characteristic echocardiographic depiction of a cardiac lymphoma is a hypoechoic space-occupying lesion or lesions in the right atrium or right ventricle with a pericardial effusion. Occasionally, the tumor may present as a pericardial effusion alone. Malignant features are indicated by a location far from the interatrial septum, a broad base, and invasion of contiguous structures. When tumors occur intramyocardially, a local area of abnormal echogenicity, atypical wall thickness, and regional hypokinesis may be detected. CCT demonstrates an intramyocardial mass or intracavitary filling defect that is hypoattenuating or isoattenuating relative to myocardium, and enhances heterogeneously after contrast injection. CMR provides the best anatomic depiction of the noninvasive imaging techniques for cardiac lymphomas, particularly when delineating pericardial and myocardial invasion. Cine sequences are especially helpful in distinguishing tumor from fluid in

Multimodality Imaging in Cardiovascular Medicine

the pericardial space and can aid in identifying blood or proteinaceous material in the pericardial fluid. On T1-weighted sequences, lymphomas are isointense to hypointense compared with myocardium, and are isointense to hyperintense on T2-weighted and proton Â�density–weighted images. On first-pass imaging, contrast enhancement is heterogeneous and intense, and delayed enhancement images show a heterogeneous pattern. Myocardial tagging, a technique commonly used to assess regional myocardial function, can aid in distinguishing contractile from noncontractile myocardium when evaluating intramyocardial masses [33]. Pericardial Mesothelioma Pericardial mesotheliomas originate from pericardial mesothelial cells, and are the most common primary pericardial tumor. The tumor spreads locally and frequently obliterates the pericardial space, but does not invade the epicardium to any significant degree. Patients frequently present with signs and symptoms of acute or chronic pericarditis (chest pain, dyspnea), constrictive pericarditis (including right heart failure), or cardiac tamponade.

Imaging Characteristics TEE and TTE demonstrate a thickened pericardium, often appearing as thickened layers of parietal and visceral pericardium, separated by an effusion. Occasionally, the entire pericardial space is filled with the solid tumor material. CCT may be the optimal technique for assessment of mesotheliomas, since the boundaries of tumor and solid material are very well seen. CMR can define the pericardial borders and fluid well, but the variable intensities on T1- and T2-weighted imaging can result in confusion with chronic, or Â�effusive-constrictive pericarditis. Metastatic Disease In general, metastatic tumors to the heart occur much more commonly than primary tumors [4]. The most frequent metastatic tumors involving the cardiac structures (in order of occurrence) are those of the lung, breast, lymphoma, and leukemia. However, the tumors with the greatest propensity for cardiac involvement are melanoma, malignant germ cell tumor, leukemia, lymphoma, lung cancer, and sarcoma [2,4]. By logical extension, metastatic cardiac disease is usually a consequence of the patient’s known primary tumor, though primary lymphoma and sarcoma may only be determined by surgery or autopsy findings.

Patterns of Involvement The most frequent site of involvement for metastatic tumors is the pericardium (both visceral and parietal

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F igure 2 0 . 6â•…Leukemic infiltrate—axial plane enhanced cardiac computed tomography (CCT, left) and balanced steady-state free precession (right) cardiac magnetic resonance (CMR) images in the same patient show poorly enhancing, confluent, nodular soft tissue masses infiltrating both atria and the base of the left ventricle (arrows). CCT well depicts the location and extent of the soft tissue abnormalities. However, the advantages of CMR for clinical evaluation include defining and quantifying the functional effects of the infiltrating mass on the ventricles and valves.

layers). Intrapericardial masses, with or without associated pericardial effusions, are usually seen. Effusiveconstrictive pericarditis, with persistence of constrictive physiology after removal of pericardial fluid, is a typical presentation. It is common for lung and breast cancers to affect the heart by direct extension from locations surrounding the heart, and rare for metastatic tumors to produce intracavitary or endocardial masses. Hematogenous metastatic disease is a common mechanism for melanoma and lymphoma to spread to the heart, and can also be seen with leukemia and sarcomas, though leukemic Â�pericardial masses with hemorrhagic effusions can be present as well. All 4 cardiac chambers can be affected by leukemic infiltration, sometimes quite extensively (Figure 20.6). Melanoma affects the heart diffusely, and frequently involves all 4 chambers and the myocardium [34]. Lung or mediastinal tumors can invade the heart via the pulmonary veins, and masquerade as a left atrial mass (occasionally with obstructive physiology), though the pericardial presentations are most frequent (Figure 20.7). It is very important, however, to recognize that the Â�origin of a left atrial mass may be outside the heart itself. Sarcomas can extend to the right atrium from the superior and inferior vena cavae, and it is not uncommon for hepatocellular, renal cell carcinomas, or lung cancer metastatic to the adrenal gland (or associated tumor thrombus) to be associated with right atrial masses via spread from the inferior vena cava (Figure 20.8).

the impact of the metastatic cardiac disease. CCT is especially helpful in identifying intramyocardial masses and pericardial tumors. However, CMR has several advantages over the other techniques in detecting metastatic disease, particularly with pericardial involvement. CMR provides outstanding discrimination of the tumor from pericardial fluid and can evaluate the cardiac chambers over the course of the cardiac cycle. This feature, similar to echo, can provide dynamic hemodynamic evaluation to assess for chamber collapse or the characteristic

Imaging Characteristics TTE and TEE can detect intrapericardial tumors and aid in determining the pattern of involvement, particularly with caval or pulmonary vein extension of tumor. However, given echocardiography’s limited field of view, the actual identification and extent of the primary tumor is very limited. CCT provides tomographic images that are very important in defining the location, extent, and potential identification of the primary tumor, as well as

F igure 2 0 . 7 â•…Lung cancer metastatic to pericardium—axial plane,

enhanced cardiac computed tomography (CCT) image reveals a large loculated pericardial effusion (PE) with nodular, enhancing, soft tissue consistent with metastatic involvement of pericardium. Arrowheads depict parietal pericardium. Small soft tissue components and surrounding lung involvement are better shown with CCT. However, the functional effects of pericardial disease would be better quantified with cardiac magnetic resonance. Note bilateral pleural effusions (P) and atelectatic lung tissue as well.

32 8

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A

B

Benign Conditions Masquerading as Tumors Nonpathologic conditions can frequently mimic cardiac tumors and may present in similar ways with comparable symptoms. The goal of noninvasive imaging is to differentiate the benign from pathologic conditions and to prevent unnecessary surgical or invasive studies when possible. Several common disorders often mistaken for cardiac tumors include thrombi, lipomatous hypertrophy (LH) of the interatrial septum, inferior compression of the atria (a “pseudomass” caused by an enlarged liver, hiatal hernias, or extracardiac masses), coronary artery aneurysms, or postoperative inflammatory changes.

Thrombus

F igure 2 0 . 8 â•…Inferior vena cava tumor thrombus extending to the

right atrium—axial plane, post-contrast, T1-weighted magnetic resonance images showing extensive low–signal intensity tumor in the right kidney (A, arrows) extending into the right renal vein and IVC and extending to the right atrium (B, white arrow). The extent of IVC involvement is more apparent on the coronal plane post-contrast, T1-weighted images (B, bracket, arrowheads). Enhanced computed tomography would demonstrate low-density signal in these locations and could be used with equal reliability to evaluate thrombus.

diastolic bounce seen in pericardial constriction. The location, mobility, and width of the base of tumor attachment can be readily identified with CMR, which is very important for differentiating tumor from thrombus or artifacts related to slow blood flow or incomplete contrast mixing in the right atrium (as is frequently seen with CT). CMR’s tissue characterization capabilities are a particular strength in that patterns of signal intensities may be used to identify tumors. The majority of tumors appear hypointense on T1-weighted imaging, with greater signal intensity in T2-weighed imaging, and enhance with Â�gadolinium-based contrast agent administration. However, melanoma has a high T1-weighted signal intensity and is brighter than other tumors on T2-weighted imaging due to paramagnetic metal binding by melanin within the tumors [35,36].

The most common condition mistaken for a cardiac tumor is intracardiac thrombus. Thrombi can occur in any cardiac chamber, but typically occur in the atria when atrial fibrillation is present (Figure 20.9), or in the ventricular apices with severe global right or left ventricular dysfunction, or at the left ventricular apex when a wall motion abnormality is present (postinfarction, Chagas disease, or endomyocardial fibrosis) (Figure 20.10). Right atrial thrombus can be seen as a cast of the leg veins and a serpiginous mass or extending from the inferior vena cava, often with pulmonary emboli (Figure 20.11). The imaging characteristics of thrombus material vary by modality and can change considerably depending on age. On TTE and TEE, the location of

Figure 20.9â•…Right atrial thrombus—axial plane, 4-chamber view, postcontrast, T1-weighted image showing low-signal, nonenhancing mass along the lateral right atrial wall consistent with thrombus (arrow). Note that the small degree of signal intensity heterogeneity is from blood products of varying stages of evolution and age.

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F igure 2 0 . 1 0 â•… (A) Cardiac magnetic resonance (CMR) evaluation of left ventricular (LV) thrombus—axial plane, 4-chamber view, post-Â�contrast

T2-weighted and (B) double-inversion (black-blood) CMR image showing irregular nonenhancing thrombus (arrows) along the anteroseptum and apex in a dilated cardiomyopathy (left) and a postinfarction apical aneurysm (right), respectively. (C) Cardiac computed tomography (CCT) assessment of apical LV thrombus—axial plane, enhanced CCT image demonstrating a postinfarction apical aneurysm with dilation and calcification. A hypoattenuating filling defect in the apex represents thrombus (T). Calcium is seen as the thin, semicircular, bright area adjacent to the apical thrombus. The apical dilation and thrombus are also well seen with CMR. Both CCT and CMR can demonstrate apical dyskinesis, but calcium is better depicted on CCT.

the mass provides useful clues as to the origin of the mass. Most atrial thrombi are posteriorly located, are commonly seen in the appendage, and are best identified on TEE. Apical thrombi are more difficult to visualize with TEE, and TTE provides the best depiction, although, not uncommonly, questions still remain as to the size and location of the mass. On CCT, thrombi are nonenhancing, homogeneous, and hypodense masses often associated with a chamber wall [22]. CMR can identify thrombi and provide information about their relative age better than other techniques. Acute thrombus is bright on both T1- and T2-weighted

F igure 2 0 . 1 1 â•…Enhanced axial computed tomography (CT) images revealing bilateral central pulmonary emboli (PE) and associated right heart enlargement (left panel) with septal flattening due to elevated right heart pressures. A serpiginous right atrial thrombus (left panel, arrow) is present. Note proximal thrombi in the left and right pulmonary arteries (right panel, arrows), and extension into a branch pulmonary artery (right arrow). Cardiac magnetic resonance is not as effective as CT for detecting pulmonary emboli, in part due to susceptibility effects from surrounding gas in the lungs. CT is the preferred method for PE evaluation.

sequences, while subacute thrombus is bright on T1-weighted imaging but with areas of hypointensity on T2-weighted imaging due to the presence of organizing areas containing methemoglobin. Chronic Â�organized thrombus will exhibit low signal intensity on T1- and T2-weighted sequences due to presence of hemosiderin and little water content [37]. Contrast enhancement behavior of suspected thrombi provides additional clues as to the etiology of the mass. After contrast injection, thrombi show no enhancement on first-pass imaging, but show little late enhancement except at the surface, where some neovascularization

330

of thrombus may occur over time. Tumors typically will show evidence of late enhancement, but the pattern may be heterogeneous.

LH of the Interatrial Septum LH is not an actual tumor, but simply an accumulation of mature adipocytes that lack a capsule. The condition is more typically seen in older obese individuals with large amounts of mediastinal fatty deposition, and is often incidentally found in normal individuals. On echocardiography, the condition manifests as a highly echogenic bilobed septal mass that spares the thin fossa ovalis, and typically extends prominently into the upper to mid-right atrium. CT demonstrates a signal intensity comparable to subcutaneous fat. The abnormally thickened septum is generally greater than 2 cm in the transverse dimension with a characteristic Hounsfield density equal to fat. The appearance of the interatrial septum is typically described as a Â�dumbbell-shaped mass. On CMR, the fatty tissue demonstrates findings similar to that of lipomas— increased signal intensity on T1-weighted images, and slightly decreased signal intensity on T2-weighted images. The characteristic CMR finding of LH is a marked decrease in signal intensity of the mass with a fat saturation sequence (Figure 20.12).

Multimodality Imaging in Cardiovascular Medicine

Pericardial Cysts Pericardial cysts are generally asymptomatic congenital abnormalities that are incidentally discovered on an imaging modality performed for other reasons. The cysts generally present as loculated fluid-filled structures separate from the pericardium, have a benign course, and remain stable for many years, but occasionally require definitive therapy. The cysts generally occur at the right costophrenic angle, but can become quite large and occasionally encircle the entire heart. The threshold for therapy is usually when intrapericardial pressure rises to the point of impairing chamber filling, or if significant diastolic chamber collapse occurs. Exertional dyspnea may be an early finding signifying a rise in intrapericardial pressure. TTE and TEE are generally useful in identifying the cyst and assessing its hemodynamic impact with 2D echo and Doppler techniques. The fluid-filled structures are well seen, but the full circumferential extent and size of the cyst may not be well defined by echo. CCT demonstrates a localized fluid-Â�density collection (close to zero Hounsfield units) that does not enhance on first-pass or delayed imaging. CMR demonstrates characteristic signal properties for fluid-containing structures: a homogeneous collection with low-intensity signal on T1-weighted imaging and high intensity on T2-weighted sequences. There is no contrast enhancement on first-pass or delayed imaging. If proteinaceous material is present within the cyst, both T1- and T2-weighted images will exhibit high signal intensity [39].

Postoperative Inflammatory Changes

2 0 . 1 2 â•…Lipomatous hypertrophy (LH) of the interatrial post-contrast, T1-weighted images showing Â� septum—Fat-suppressed, hypoenhancing, low–signal intensity mass in the interatrial septum (cephalad portion) with similar signal characteristics to fat (arrow). Cardiac computed tomography could also be used to depict the focal low density mass; however, the edges of the lesion in LH are often better appreciated with the greater soft tissue contrast of cardiac magnetic resonance. F igure

Occasionally postoperative mediastinal and paracardiac inflammatory tissue can resemble a cardiac tumor. In Figure 20.13, an example of such a situation is illustrated. A patient presented with chest discomfort several months after a sternotomy. The TTE showed a mass adjacent to the atrioventricular groove that appeared to compress the right coronary artery (RCA). CT confirmed the mass and the fact that it encircled the RCA. Its attenuation characteristics were that of tissue density, and there was signal enhancement with contrast. On CMR, tissue properties similar to an angiosarcoma were found; however, no Â�evidence of tissue invasion or pericardial effusion was seen. A biopsy demonstrated histiocytic fibrosis, that is, inflammatory scar tissue related to the prior surgery, and follow-up scans confirmed a progressive reduction in size of the mass. While the tissue signal properties and enhancement characteristics may be similar to that of a tumor, the lack of tissue invasion or pericardial effusion, benign course, and decreased size over time are more consistent with inflammatory tissue.

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F igure 2 0 . 1 3 â•… Postsurgical inflammatory changes—axial plane enhanced computed tomography (left) and 4-chamber balanced steady-state free precession (right) images demonstrate enhancing soft tissue (arrows) in the right atrioventricular groove that appears to be involving the myocardium and compressing the right coronary artery. Note evidence of previous sternotomy/ sternal wires. Though these characteristics and location could be consistent with an angiosarcoma, a biopsy demonstrated histiocytic fibrosis or inflammatory scar tissue due to prior sternotomy. The mass was found to decrease in size on subsequent examinations with no negative outcomes.

jâ•… CONCLUSIONS Noninvasive imaging tools such as echocardiography, CCT, CMR, and cardiac nuclear imaging provide detailed information on cardiac masses and facilitate creation of a working diagnosis when clinicians are presented with an unknown lesion. The primary goal of these techniques is to distinguish normal structures and their variants from pathologic conditions, and then to differentiate benign tumors from malignancies. Further refinement of clinical and imaging strategies such as the assessment of patient demographics, oncologic history, and the value of various tissue signal properties or contrast enhancement behavior will inform decisions on selection of a particular imaging modality. While these tools often provide complementary information, data interpretation as related to an individual patient is vital. Mass location, morphology, tissue characterization (cystic/solid, calcifications, and the presence of fat, hemosiderin, or fibrous tissue), and degree of invasiveness are all cardinal features distinguishing lesions from one another. Rational use of multimodality imaging techniques is dependent on sound clinical acumen, prudent interpretation of initial studies, and thoughtful selection of advanced imaging modalities based on the highest yield method for the unresolved questions. Considerate use of our limited health care resources will ensure that future patients will continue to receive the benefits that noninvasive imaging provides.

jâ•… REFERENCES â•‡ 1. Reynen K. Cardiac myxomas. N Engl J Med. 1995;333: 1610–1617. â•‡ 2. Burke A, Virmani R. Tumors of the Heart and Great Vessels. Washington, DC: Armed Forces Institute of Pathology; 1996.

â•‡ 3. Roberts W. Primary and secondary neoplasms of the heart. Am J Cardiol. 1997;80:671–682. â•‡ 4. Lam K, Dickens P, Chan A. Tumors of the heart. A 20-year experience with review of 12 485 consecutive autopsies. Arch Pathol Med. 1993;117:1027–1031. â•‡ 5. Meng Q, Lai H, Lima J, et al. Echocardiographic and pathologic characteristics of primary cardiac tumors: a study of 149 cases. Int J Cardiol. 2002;84:69–75. â•‡ 6. Markel M, Waller B, Armstrong W. Cardiac myxoma. A review. Medicine. 1987;66:114–125. â•‡ 7. Silverman NA. Primary cardiac tumors. Ann Surg. 1980;191:127–138. â•‡ 8. Carney J, Gordon H, Carpenter P, et al. The complex of myxomas, spotty pigmentation, and endocrine overactivity. Medicine. 1985;64:270–283. â•‡ 9. Freedberg RS, Kronzon I, Rumancik WM, Liebeskind D. The Â�contribution of magnetic resonance imaging to the evaluation of intracardiac tumors diagnosed by echocardiography. Circulation. 1988;77:96–103. 10. Grebenc M, Rosado de Chrisenson M, Burke A, et al. Primary cardiac and pericardial neoplasms: radiologic-pathologic correlation. Radiographics. 2000;20:1071–1103. 11. Matsuoka H, Hamada M, Honda T, et al. Morphologic and histologic characterization of cardiac myxomas by magnetic resonance imaging. Angiology. 1996;47:693–698. 12. Masui T, Takahashi M, Miura K, et al. Cardiac myxoma: identification of intratumoral hemorrhage and calcification on MR images. AJR Am J Roentgenol. 1995;164:850–852. 13. Ragland M, Tak T. The role of echocardiography in diagnosing space-occupying lesions of the heart. Clin Med Res. 2006;4:22–32. 14. Kamiya H, Ohno M, Iwata H, et al. Cardiac lipoma in the interventricular septum: evaluation by computed tomography and magnetic resonance imaging. Am Heart J. 1990; 119:1215–1217. 15. Hananouchi GI, Goff WB II. Cardiac lipoma: 6-years follow-up with MRI characteristics, and a review of the literature. Magn Reson Imaging. 1990;8:825–828. 16. Ruggiero NJ, Doherty JU, Ferrari VA, Hansen CL. Myocardial perfusion defect caused by intramyocardial lipoma. J Nucl Cardiol. 2008;15:286–289. 17. Edwards FH, Hale D, Cohen A, Thompson L, Pezzella AT, Virmani R. Primary cardiac valve tumors. Ann Thorac Surg. 1991;52:1127–1131. 18. Klarich KW, Enriquez-Sarano M, Gura GM, et al. Papillary fibroelastoma: echocardiographic characteristics for diagnosis and pathologic correlation. J Am Coll Cardiol. 1997;30:784–790.

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19. Wintersperger B, Becker C, Gulbins H, et al. Tumors of the cardiac valves: imaging findings in magnetic resonance imaging, computed tomography, and echocardiography. Eur Radiol. 2000;10;443–449. 20. Jahnke C, Hamdan A, Fleck E, Paetsch I. Tissue characterization of a suspected aortic valve fibroelastoma with cardiac magnetic resonance imaging. Circ Cardiovasc Imaging. 2008;1(1):87–88. 21. Kusano K, Ohe T. Cardiac tumors that cause arrhythmias. Card Electrophysiol Rev. 2002;6;174–177. 22. Restrepo C. Largoza A, Lemos D, et al. CT and MR imaging findings of benign cardiac tumors. Curr Prob Diagn Radiol. 2005;34:12–21. 23. Rienmuller R, Tiling R. MR and CT for detection of cardiac tumors. Thorac Cardiovasc Surg. 1990;38(suppl 2):168–172. 24. Conti VR, Saydjari R, Amparo EG. Paraganglioma of the heart. The value of magnetic resonance imaging in the preoperative evaluation. Chest. 1986;90:604–606. 25. Shapiro B, Copp JE, Sisson JC, Eyre PL, Wallis J, Beierwaltes WH. Iodine-131 metaiodobenzylguanidine for the locating of suspected pheochromocytoma: experience in 400 cases. J Nucl Med. 1985;26:576–585. 26. Fisher MR, Higgins CB, Andereck W. MR imaging of an intrapericardial pheochromocytoma. J Comput Assist Tomogr. 1985; 9:1103–1105. 27. Araoz PA, Ecklund HE, Welch TJ, et al. CT and MR imaging of primary cardiac malignancies. Radiographics. 1999;19:1421–1434. 28. Putnam JB Jr, Sweeney MS, Colon R, Lanza LA, Frazier OH, Cooley DA. Primary cardiac sarcomas. Ann Thorac Surg. 1991; 51:906–910.

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29. Burke AP, Cowan D, Virmani R. Primary sarcomas of the heart. Cancer. 1992;69:387–395. 30. Kim EE, Wallace S, Abello R, et al. Malignant cardiac fibrous histiocytomas and angiosarcomas: MR features. J Comput Assist Tomogr. 1989;13:627–632. 31. Ceresoli GL, Ferreri AJ, Bucci E, et al. Primary cardiac lymphoma in immunocompetent patients: diagnostic and therapeutic management. Cancer. 1997;80:1497–1506. 32. Dorsay TA, Ho VB, Rovira MJ, et al. Primary cardiac lymphoma: CT and MR findings. J Comput Assist Tomogr. 1993;17: 978–981. 33. Bouton S, Yang A, McCrindle BW, et al. Differentiation of tumor from viable myocardium using cardiac tagging with MR imaging. J Comput Assist Tomogr. 1991;15:676–678. 34. Waller BF, Gottdiener JS, Virmani R, Roberts WC. The “charcoal heart”; melanoma to the cor. Chest. 1980;77:671–676. 35. Mousseaux E, Meunier P, Azancott S, Dubayle P, Gaux JC. Cardiac metastatic melanoma investigated by magnetic resonance imaging. Magn Reson Imaging. 1998;16:91–95. 36. Enochs WS, Petherick P, Bogdanova A, Mohr U, Weissleder R. Paramagnetic metal scavenging by melanin: MR imaging. Radiology. 1997;204:417–423. 37. Doons G, Higgins C. MR imaging of cardiac thrombi. J Comput Assist Tomogr. 1986;10:415–420. 38. Paydarfar D, Krieger D, Dib N, et al. In vivo magnetic resonance imaging and surgical histopathology of intracardiac masses: distinct features of subacute thrombi. Cardiology. 2001;95:40–47. 39. Frank H, Globits S. Magnetic resonance imaging evaluation of myocardial and pericardial disease. J Magn Reson Imaging. 1999;10:617–626.

Index

-MyC, on 14q1, 117 2,3,5-triphenyltetrazolium chloride– stained slice, 63–64 3-D contrast-enhanced MRA acquisition parameter for, 212 with time-resolved angiography, steps for, 217 3-D gradient echo angiographic sequences, 211–212 13 N-ammonia, 6, 9 15-(p-[iodine-123]iodophenyl-3-(R,S) methylpentadecanoic acid (BMIPP), 65 [18F]2-deoxy,2-fluoroglucose imaging with PET, 82–83, 277 18F-Fluorodeoxyglucose (FDG), 149, 260, 277 31 P-NMR spectroscopy, 66 64-multidetector computed tomography (MDCT) in mitral regurgitation, 168 64-row detector CTPA protocol for evaluating patients suspected acute pulmonary embolism, 106 82 Rubidium, 6, 8, 9, 12, 83, 142, 149, 150 99m Tc-pyrophosphate, 53 99m Tc sestamibi, 7, 31, 54, 55, 60, 65, 82, 140 99m Tc-tetrofosmin, 54, 55 99m Technetium (99mTc), 60, 93, 140, 231 111 In-antimyosin, 53, 54 [123I]--methylp-iodophenylpentadecanoic acid (BMIPP), 83–84 123 I-metaiodobenzylguanidine (mIBG), 85 131 metaiodobenzylguanidine (131I-MIBG), 323 201 Thallium, 55, 60, 277, 140, 149, 231 459delC, 133 Abdominal coarctation, 221 Abnormal papillary muscle morphology, 130, 132, 133 ACCF/AHA Consensus Document, 302–303 ACCURACY (Assessment by Coronary Computed Tomographic Angiography of Individuals Undergoing Invasive Coronary Angiography), 37

Acquired cardiomyopathies myocarditis, 274–275 Acquisition parameters, 222 Acute aortic syndromes (AAS). See Aortic dissection Acute chest pain evaluation, MPI in, 31 Acute coronary syndromes (ACSs), 58 imaging methods for detecting, 59 noninvasive imaging diagnosis and prognosis in patients cardiac magnetic resonance imaging, 66–67 computed tomography, 67–68 echocardiography, 61–64 single photon emission computed tomography, 64–66 pathophysiology and implications for imaging, 59 Acute infarction cardiac magnetic resonance studies in, 76–77 Acute mitral regurgitation, 47 Acute myocardial infarction (AMI), 58 contributes to post-MI risk stratification, 71–72 Acute pulmonary embolism. See Pulmonary embolism (PE) Acute ST elevation myocardial infarctions (STEMI) cardiac CT, 52 diagnosis and management, 53 risk stratification and prognosis, 53, 54 cardiac magnetic resonance diagnosis and management, 50–51 risk stratification and prognosis, 51–52 clinical and differential diagnosis of, 45 echocardiography diagnosis and management, 46–48 risk stratification and prognosis, 48–50 imaging role, 46 nuclear techniques infarct avid imaging, 53–54 myocardial perfusion imaging, 54–55 risk stratification and prognosis, 55 pathophysiology, 45

Acute stress-induced cardiomyopathy, 51 Adenosine, 140, 143, 145 Adenosine stress cardiovascular magnetic resonance, 147, 148 Administration of contrast, 214 Adriamycin, 119 Agatston score, 301 Alcohol septal reduction cardiac magnetic resonance, 134 echocardiography, 131–132 American College of Cardiology (ACC) and American Heart Association (AHA) guidelines, 1, 13, 24, 46, 183, 230 American Heart Association on noninvasive coronary imaging (2008), 241 American Society of Anesthesiologist index, 229 American Society of Echocardiography guidelines, 174 AMP kinase, 261 Amyl nitrite, 130, 131 Amyloid cardiomyopathy, 118–119 Amyloidosis, 134, 275–276 restrictive cardiomyopathy, 258–259 secondary cardiomyopathies, 275–276 Anatomical imaging techniques restenosis assessment, 96 magnetic resonance imaging, 98–99 multidetector row computed tomography angiography (MDCT), 96–98 Anderson–Fabry disease (AFD), 261, 279–280 Aneurysms, 240 and dissection, 219, 220 and endovascular stent evaluation, 223–224 Angina, typical. See Chest pain Angiosarcomas, 320, 325 Ankle-brachial index (ABI), 209 Anterior tibial artery, 210, 211 Aorta, coarctation of, 244–246 Aorta size measurement, 199–200 Aorta-iliac disease, 217 Aortic dilatation, 193 333

Index

334

Aortic dissection, 48, 49 aorta size measurement, 199–200 aortic insufficiency, 200, 201 aortic rupture, 200, 202 branch vessel involvement assessment, 199 catheter angiography, 205–206 chest radiography, 203 classification, 196 computed tomography, 204 definitions, 192 differentiation from IMH and PAU, 197–198 echocardiography, 203–204 electrocardiography, 201 epidemiology and pathophysiology, 192–195 magnetic resonance imaging, 204–205 presentation, 195 treatment, 197 true and false lumina, 198–199 localization of communications between, 199 Aortic insufficiency, 200, 201 Aortic regurgitation (AR), 174 cardiac computed tomography, 178 cardiac magnetic resonance imaging, 176–177 color and continuous-wave Doppler echocardiography, 174–175 with dyspnea, 122 echocardiography, 174–176 etiologies of, 175 severity of, 175 Aortic rupture, 200, 202 Aortic stenosis (AS), 122, 168–169 cardiac computed tomography, 172–174 cardiac magnetic resonance imaging, 171–172 echocardiography, 169–171 etiologies of, 169 severity of, 174 Aortic valve (AV) aortic regurgitation. See Aortic regurgitation (AR) aortic stenosis. See Aortic stenosis (AS) Aortobifemoral grafts, 218 Arg403Gln and Arg719Gln mutations, 127 Arrhythmias, 16. See also Atrial arrhythmias Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D), 267–268 Arterial age, 301 Arteriovenous fistulas, 221 Arteriovenous malformations (AVMs), 220–221

Arteritis and inflammatory disorders, 210 Asymmetric septal hypertrophy (ASH), 117 Atherosclerosis. See Noninvasive atherosclerosis imaging Atherosclerosis Risk in Communities (ARIC) study, 308 Atherosclerotic peripheral arterial disease, 209, 210, 216–217, 223 Atrial arrhythmias atrial mechanical function, 287, 288 atrial remodeling, 288 atrial size, 286–287 atrial structure and function, 286 atrial thrombi and thromboembolic risk, 285–286 catheterization, 290–291 early detection of complications, 292 esophageal injury, avoiding, 291–292 gross cardiac landmarks and anatomy, 288–289 image integration with electroanatomical mapping systems, 292–293 monitoring of catheter position, 291 multimodality imaging in, 284–295 postprocedural imaging esophageal injury, 294–295 predicting success of procedure, 293–294 pulmonary vein stenosis, 294 preprocedural imaging initial assessment with echocardiography, 284–285 procedural imaging real-time cardiac imaging, 290 pulmonary veins anatomy, 289–290 Atrial fibrillation (AF). See Atrial arrhythmias Atrial septal defects (ASDs), 123, 242–244 Atrial stunning, 287 Atrioesophageal fistula, 291, 293 Atrio-ventricular valve regurgitation as cause of dyspnea, 120–122 Baffes procedure, 246 Bayesian analysis, 1 Benign cardiac masses, 318–319 conditions masquerading as tumors, 328 lipomatous hypertrophy (LH) of interatrial septum, 330 pericardial cysts, 330 postoperative inflammatory changes, 330, 331 thrombus, 328–330 fibromas, 322–323, 324

hemangiomas, 323–324 lipomas, 322 myxomas, 317, 318, 321–322 papillary fibroelastomas, 322, 323 paragangliomas, 323 Beta-blockers, 197 cardioprotective effect of, 234–235 Bicuspid aortic valve (BAV) disease, 169, 170–171, 193 Bidirectional superior cavopulmonary connection (BSCC), 248 Biphasic response, 150 Bjork-Shiley valve, 173 Blood oxygen level dependency (BOLD) imaging, 148 Bogalusa Heart Study, 308 Brachial artery reactivity testing (BART), 310–311 Buerger’s disease, 218, 223 CADILLAC risk score, 72 Calcific aortic valve disease, 168 Canadian Cardiovascular Society index, 229 Carcinoid disease, 182 Cardiac amyloidosis, 118 Cardiac computed tomography (CCT), 162 acute MI, 77–78 acute STEMI, 52–53 aortic regurgitation, 178 aortic stenosis, 172–174 benign cardiac masses fibromas, 318, 323 hemangiomas, 318, 324 lipomas, 318, 322 myxomas, 317, 318, 321 papillary fibroelastomas, 318, 322, 323 paragangliomas, 318, 323 bypass grafts evaluation, 4–5 cardiac masses, 316 cardiomyopathy, 266–267, 271, 272 constrictive pericarditis (CP), 255 coronary artery calcium (CAC) scoring, 2 coronary artery stents evaluation, 4, 5 coronary CT angiography, 2–4, 5 diagnosis and management, 53 malignant cardiac masses angiosarcomas, 325 lipomatous hypertrophy (LH) of interatrial septum, 319, 330 lymphomas, 326 metastatic disease, 327 pericardial cysts, 319, 330 pericardial mesothelioma, 326 postoperative inflammatory changes, 319, 330 thrombus, 319, 329

Index

mitral regurgitation, 168 mitral stenosis, 162 preoperative testing in noncardiac surgery, 232–234 pulmonic valve, 184 risk stratification and prognosis, 53, 54 tricuspid regurgitation, 182 Cardiac imaging, in systolic heart failure, 114–115 Cardiac magnetic resonance (CMR) imaging. See also Magnetic resonance imaging (MRI) aortic regurgitation, 176–177 aortic stenosis, 171–172 benign cardiac masses fibromas, 318, 323 hemangiomas, 318, 324 lipomas, 318 myxomas, 317, 318, 321–322 papillary fibroelastomas, 318, 322 paragangliomas, 318, 323 cardiac masses, 316–317 cardiomyopathy, 264–266, 268, 270–271, 272, 273, 275, 276, 280 congenital heart disease (CHD), 240–241, 243–244, 245–246, 247–248, 249 constrictive pericarditis (CP), 254–255 detection of regional wall motion abnormalities, 142–143 diagnosis and management late gadolinium enhancement (LGE), 50–51 T2-weighted techniques, 51 in hypertrophic cardiomyopathy (HCM) cardiac morphology evaluation, 132–133 differential diagnosis, role in, 134 myocardial fibrosis evaluation, 133–134 regional function and flow characteristics evaluation, 133 success of treatment, 134 infarct size assessment, 75–77 LV function assessment, 75 malignant cardiac masses angiosarcomas, 325 lipomatous hypertrophy (LH) of interatrial septum, 319, 330 lymphomas, 326 metastatic disease, 327–328 pericardial cysts, 319, 330 pericardial mesothelioma, 326 postoperative inflammatory changes, 319, 330 thrombus, 319, 329 mitral regurgitation, 165–168

335

mitral stenosis, 161–162 noninvasive imaging diagnosis and prognosis in patients with suspected ACSs, 66–67 preoperative testing in noncardiac surgery, 233–235 pulmonic valve, 184 restrictive cardiomyopathy (RCM), 257, 258, 260, 261 risk stratification and prognosis areas at risk and infarct size, 51–52 function improvement, LV remodeling, and post-MI prognosis, 52 tricuspid regurgitation, 181–182 viability assessment late gadolinium enhancement (LGE), 151 wall thickness and contractile reserve, 151 Cardiac masses benign, 317, 318–319 fibromas, 322–323, 324 hemangiomas, 323–324 lipomas, 322 myxomas, 317, 321–322 papillary fibroelastomas, 322, 323 paragangliomas, 323 cardiac computed tomography, 316 cardiac magnetic resonance, 316–317 echocardiography, 316 malignant cardiac masses benign conditions masquerading as tumors, 328–331 lymphomas, 326 metastatic disease, 320, 326–328 pericardial mesothelioma, 320, 326 sarcomas, 324–326 Cardiac risk estimation, 229–230 Cardiomyopathies acquired cardiomyopathies myocarditis, 274–275 amyloid, 118–119 cardiac computed tomography, 266–267 cardiac magnetic resonance, 264–266 differential diagnosis of, 263–280 echocardiography, 263–264, 265 primary cardiomyopathies arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D), 267–268 dilated cardiomyopathy (DCM), 272–274 hypertrophic cardiomyopathy (HCM), 268–271 left ventricular noncompaction, 271–272 secondary cardiomyopathies amyloidosis, 275–276

Anderson-Fabry disease, 279–280 iron-overload cardiomyopathy, 277–279 sarcoidosis, 276–277, 278 Cardioprotective medical therapy beta-blockers and statins, 234–235 Cardiotoxic agents, 119 Cardiovascular CT angiography (CCTA), 61 Cardiovascular Health Study (CHS), 308 Carney syndrome, 317 Carotid intima-media thickness (CIMT), 307 definition and measurement of, 307–308 role in risk assessment, 309–310 surrogate marker for atherosclerosis risk, 308–309 Carpentier classification of mitral regurgitation, 163 Catecholamines, 323 Catheter angiography (CA) aortic dissection, 205–206 Catheter pulmonary angiography for pulmonary embolism (PE), 105 Catheterization, 290–291 Chemotherapeutic agents, 119 Chest pain. See also Coronary artery disease (CAD) aorta dissection, 195 conceptual framework, 1 general considerations in pretest evaluation of patients with, 22–42 noninvasive imaging approaches exercise electrocardiography, 1–2 cardiac CT, 2–5 stress echocardiography, 5–6 stress nuclear imaging, 6–11, 12 stress cardiac magnetic resonance imaging, 11–13 patients, selecting strategy in with known CAD, 17 without known CAD, 13–17 Chest radiography aortic dissection, 203 Chest X-ray (CXR) congenital heart disease (CHD), 238–239, 244, 246, 248–249 Cholesterol Lowering Atherosclerosis Study (CLAS), 308 Chronic ischemia, 139 Chronic myocardial ischemia and viability assessment. See Myocardial ischemia assessment Cine CMR imaging, 143 Cine gradient-echo sequences, 161 Claudication. See Peripheral arterial disease (PAD)

Index

336

Clinical decision rules with pulmonary embolism (PE), 103–105 Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial, 29, 30 Complex congenital heart disease (CHD) defined, 238 functional single ventricles, 248–250 transposition of the great arteries (TGA), 246–248 Complex cyanotic congenital heart disease, 271 Compression ultrasound (CUS), 108–109 Computed tomography angiography (CTA), 1. See also Coronary CT angiography (CCTA) advantages and disadvantages of, 226 aortic dissection, 204 artifacts and pitfalls, 224 clinical applications aneurysms and endovascular stent evaluation, 223–224 atherosclerotic peripheral artery disease, 223 other indications, 224 vasculitis, 223 congenital heart disease (CHD), 241 coronary, 2–4 evaluation of, 4, 5 noninvasive imaging diagnosis and prognosis in patients with suspected ACSs, 67–68 in peripheral arterial disease (PAD), 221 protocol considerations acquisition parameters, 222 contrast injection, 222 reconstruction parameters and image interpretation, 222–223 Computed tomography pulmonary angiography (CTPA), 105–108 64-row detector CTPA protocol, 105, 106 electrocardiography (ECG)-gated CTPA protocol, 106, 107 Congenital causes of aortic stenosis (AS), 169 Congenital disorders, 221 and entrapment syndromes, 221 Congenital heart disease (CHD) as cause of dyspnea, 120 complex CHD, 238 functional single ventricles, 248–250 transposition of the great arteries (TGA), 246–248 imaging principles in cardiac magnetic resonance, 240–241 chest X-ray, 238–239 computed tomography, 241

echocardiography, 239–240 radiation in cardiac imaging in, 241–242 simple CHD, 238 aorta, coarctation of, 244–246 atrial septal defects (ASD), 242–244 Congestive heart failure (CHF), 112 Constrictive pericarditis (CP). See also Restrictive cardiomyopathy (RCM) cardiac catheterization, 253–254 cardiac computed tomography, 255 cardiovascular magnetic resonance, 255–256 causes of, 252 chest X-ray, 253 clinical signs of, 253 echocardiography, 254–255 pathophysiology and presentation, 252–253 Continuity equation for aortic valve, 169 for mitral valve, 160 Contractile reserve and wall thick CMR to assess viability, 151 Contrast administration, 214 Contrast injection, 222 Contrast timing in multistation MRA, 213–214 Contrast-enhanced cardiac CT, 53 Contrast-enhanced magnetic resonance pulmonary angiography (MRPA), 107–108 Contrast-induced nephropathy (CIN) with acute aortic syndromes (AAS), 204 Coronary artery bypass grafting (CABG), 4–5, 92, 235 Coronary artery bypass surgery (CABS), 26 Coronary artery calcium (CAC) scoring, 2, 33–36, 300 and future challenges, 304, 305 clinical application in asymptomatic patient, 302–303 dual-modality CT and nuclear perfusion imaging, 10 prognostic value of, 302 rationale for risk assessment, 301 Coronary artery disease (CAD), 1 burden, 78 coronary calcium score, CTA, and MPI, approach to integrated use of, 39–41 coronary CT angiography diagnostic and prognostic impact, in different clinical populations, 36–39 role in patients with atypical chest pain, 33–36 detection and management in patients with chest pain syndromes, 39–41

future considerations, 41–42 MPI in acute chest pain evaluation, guidelines for in emergency department (ED), 31–32 presentations of intermediate likelihood of obstructive atypical chest pain and, 22 risk assessment. See Risk assessment with CAD SPECT and PET MPI for, diagnostic testing accuracy of MPI diagnostic impact, 25–26 normalcy rate, 24 referral bias, 24 SPECT MPI in specific patients with atypical clinical presentation, 32–33 systolic heart failure, 112 testing strategies selection in patients with/without known, 13–17 Coronary artery revascularization prophylaxis (CARP) trial, 235 Coronary artery stents evaluation, 4, 5 Coronary calcium score (CCS), CTA, and MPI approach to, detection and management of CAD in patients with chest pain syndromes, 39–41 Coronary CT angiography (CCTA) cardiomyopathy, 267 chest pain, 2–4, 5 to detection and management of CAD in patients with chest pain syndromes, 40 diagnostic and prognostic impact, in different clinical populations, 36–39 role in patients with atypical chest pain, 33–36 Coronary flow reserve (CFR), 9, 99 Coronary heart disease (CHD), 299. See also Noninvasive atherosclerosis imaging Coronary multidetector computed tomography angiography, 305–307 Coronary revascularization anatomical imaging techniques (restenosis assessment) magnetic resonance imaging, 98 multidetector row computed tomography angiography (MDCT), 96–98 functional imaging techniques (myocardial ischemia assessment), 92 magnetic resonance imaging, 94–96 myocardial perfusion scintigraphy (MPS), 93, 94

Index

stress echocardiography, 93–94, 95 noninvasive imaging, prognostic value of myocardial perfusion scintigraphy, 99 stress echocardiography, 99–100 prior to noncardiac surgery, 235–236 Coronary stenoses, 138 Coronary vasodilator reserve, 8 Creatinine kinase (CK), 58 CT coronary calcium scanning, 33–36 CTA-64, 2, 3 Cystic adventitial disease, 221 Danon disease, 261 Daunorubicin, 119 D-dimer tests, 104–105 DeBakey classification, 196 DECREASE I trial, 234 Deep vein thrombosis (DVT), 103 Definity, 115 Delayed hyperenhancement cardiac magnetic resonance (DHE-CMR) image, 128, 129, 133, 134 Delayed-enhancement (DE) CMR, 75, 76 Detsky modified multifactorial risk index, 229 Diabetes and renal dysfunction, 16–17 Diastolic function evaluation with hypertrophic cardiomyopathy, 129–130 Diastolic heart failure, 112 Digital subtraction angiography (DSA), 214 Dilated cardiomyopathy (DCM), 115, 116, 272–274 Dipyridamole, 132, 140, 141, 143, 145 Distal (tibioperoneal) disease, 217 Dobutamine, 131, 140, 141, 143, 145 cine CMR imaging, 143 Dobutamine stress echocardiography, 79–80, 94, 100, 150 in myocarditis, 274 Doppler echocardiography, 114, 119, 120, 122, 123 Dotarem, 144 Dual-isotope imaging, 82 Dual-modality CT and nuclear perfusion imaging, 10–11, 12 Duke Prognostic Coronary Artery Disease Index, 38 Duplex ultrasonography, 225, 226 Dutch echocardiographic cardiac risk, 230 Dyspnea atrio-ventricular valve regurgitation as a cause of dyspnea, 120–122

3 37

cardiotoxic agents, 119 congenital heart disease, 120 hypertension (HTN), left ventricular hypertrophy (LVH), and heart failure, 118 hypertrophic cardiomyopathy (HCM), 117–118 intracardiac shunts at atrial level, 123–124 LV inflow tract obstruction, 119–120 nonischemic cardiomyopathy, 115–117 parenchymal lung disease, 125 pericardial and pleural effusion, 124 pulmonary embolism, 124–125 restrictive cardiomyopathy, 118–119 semilunar valve stenosis, 122–123 semilunar valvular regurgitation, 122 systolic heart failure cardiac imaging in, 114–115 and HFNEF, 112–114 Eagle’s risk score, 229 Ebstein’s anomaly, 180, 182 Echocardiography. See also M-mode echocardiography; Stress echocardiography; Transesophageal echocardiography (TEE); Transthoracic echocardiography (TTE) 3D for mitral valve, 159, 160 3D in HCM, 132 aortic dissection, 203–204 aortic regurgitation, 174–176 aortic stenosis, 169–171 atrial fibrillation, 284–285 benign cardiac masses fibromas, 318, 323 hemangiomas, 318, 324 lipomas, 318, 322 myxomas, 317, 318, 321 papillary fibroelastomas, 318, 322 paragangliomas, 318, 323 cardiac masses, 316 cardiomyopathy, 263–264, 265, 269 congenital heart disease (CHD), 239–240, 242–243, 246–247, 249 constrictive pericarditis (CP), 254–256 diagnosis and management, with STEMI initial and differential diagnosis, 46–47 post-MI complications, 47–48 transesophageal echocardiography (TEE), 48, 49 in hypertrophic cardiomyopathy. See Hypertrophic cardiomyopathy (HCM), echocardiography

malignant cardiac masses angiosarcomas, 325 lipomatous hypertrophy (LH) of interatrial septum, 319, 330 lymphomas, 326 metastatic disease, 327 pericardial cysts, 319, 330 pericardial mesothelioma, 326 postoperative inflammatory changes, 319, 330 thrombus, 319, 328–329 mitral regurgitation, 163–165 mitral stenosis, 159–161 noninvasive imaging diagnosis and prognosis in patients with suspected ACSs, 61–64 pulmonic valve, 183 restrictive cardiomyopathy (RCM), 256–257, 261 risk stratification and prognosis, with STEMI, 48–49 low-dose dobutamine echocardiography (DE), 49–50 myocardial contrast echocardiography, 49 post-MI prognosis, 50 stress, 5–6 tricuspid regurgitation, 178–181 Edler, Inga, 158 Effective regurgitation orifice area (EROA) aortic regurgitation, 175 mitral regurgitation, 164, 166, 168 Ehlers-Danlos syndrome, 219 Electroanatomical mapping systems, image integration with, 292–293 Electrocardiography (ECG) aortic dissection, 201 role of exercise, 1–2 Electrocardiography (ECG)-gated CTPA protocol, 106–107 Electron beam computed tomography (EBCT) technology, 96, 266 Embolic disease, 218, 219 Endomyocardial fibrosis (EMF), 257–258 Endothelial dysfunction, 32, 310, 312 Endovascular stent, 218 and aneurysms, 223–224 Entrapment syndromes, 221 Eosinophilic endomyocardial disease, 257–258 Epicardial coronary artery, 45, 48, 49 Esophageal injury, 294–295 avoiding, 291–292 Ethanol injection, 131 E-to-Ea ratio, 130 European Society of Cardiology, 67, 241 Exercise ECG in ischemia assessment, 140

Index

338

Exercise radionuclide ventriculography in ischemia assessment, 140 Exercise Treadmill Test (ETT), 1, 2, 14, 16 Fabry’s disease, 134 False lumen, 192 and true lumen, 198–199 localization of communications between, 199 Fatty acid imaging with BMIPP SPECT, 83–84 FDG (18Fluorodeoxyglucose) PET techniques, 149, 150 Femoral and iliac arteries, 210 Fibromas, 322–323, 324 Fibromuscular dysplasia, 219 Fibrosarcomas, 325 Fibrous plaques, 306 Field of view (FOV), 213 Finger fracture, 158 First-pass gadolinium perfusion imaging, 144–145 Flow convergence method, 160, 164 Flow mapping, MRI, 99 Fractional flow reserve (FFR), 139 Framingham risk score (FRS) application and limitations, 299–300 Functional imaging techniques magnetic resonance imaging, 94, 95, 96 myocardial ischemia assessment, 92 myocardial perfusion scintigraphy (MPS), 93, 94 stress echocardiography, 93–94, 95 Functional single ventricles, 248–250 Functional versus Anatomic-Based testing for symptomatic individuals Underging evaLuation by MPS or CCTA: costs and clinical OUtcomeS (FABULOUS), 41 Gadolinium, 75, 144 Gadolinium-based CMR sequences, 240 Gadolinium–diethylenetriaminepentaacetic acid (Gd-DTPA), 50, 66, 144 Gadolinium enhancement, on delayed images, 11, 12 Gadovist, 144 Gallium-67 scintigraphy, 260 Gated equilibrium blood pool, 74 Gd-based contrast agents, 215 Gd-BOPTA, 144 Gd-DO3A butriol, 144 Gd-DOTA, 144 Gd-DTPA-BMEA, 144 Gd-DTPADMA, 144 Gd-HPDO3A, 144 Geneva score, 103, 104 Giant-cell arteritis, 219–220 Gibbs/truncation artifact, 221

Glycogen storage diseases, 261 Goldman cardiac risk index, 229 Gorlin syndrome, 322 GRACE risk model, 72 Graft surveillance, MRA for, 217–218 Heart failure, 148 dyspnea due to. See Dyspnea hypertension (HTN) and left ventricular hypertrophy (LVH), 118 Heart failure have normal ejection fraction (HFNEF), 111, 112, 113 Hemangiomas, 323–324 Hematogenous metastatic disease, 327 HemiFontan procedure, 250 Hibernation, myocardial, 139 Hounsfield units (HU), 301 Hypereosinophilic syndrome, 257–258 Hypertension (HTN), 111, 116, 118, 128 aorta dissection, 195 left ventricular hypertrophy (LVH) and heart failure, 118 Hypertrophic cardiomyopathy (HCM), 268–271 cardiac magnetic resonance cardiac morphology evaluation, 132–133 differential diagnosis, role in, 134 myocardial fibrosis evaluation, 133–134 regional function and flow characteristics evaluation, 133 success of treatment, 134 as cause of dyspnea, 117–118 clinical presentation, 127 echocardiography diastolic function evaluation, 129–130 differential diagnosis, role in, 128–129 during alcohol septal reduction, 131–132 during surgical septal myectomy, 132 emerging role of 3-dimensional, 132 LVOT obstruction evaluation, 131 MR evaluation, 131 myocardial perfusion scintigraphy, 132 screening and asymptomatic HCM evaluation, role in, 132 systolic function evaluation, 129 treatment strategies, facilitating, 131 ventricular morphology assessment, 127–128 Hypoplastic left heart syndrome (HLHS), 241 Hypotension aorta dissection, 195

Iliac and femoral arteries, 210 Imaging ischemia, 140 Implantable cardiac defibrillators (ICD) benefit, 84 Infarct avid imaging, 53–54 Infarct size assessment with cardiac magnetic resonance (CMR), 75–77 with myocardial perfusion imaging (MPI), 75 Inflammatory cardiomyopathy, 274–275 Inflammatory large-vessel arteritides arteriovenous malformations and fistulas, 220–221 congenital disorders, 221 entrapment syndromes, 221 magnetic resonance angiography for, 219 Inflammatory pericarditis (IP), 256 Inotropic agents, 140 Interatrial septum, 291 International Registry of Acute Aortic Dissection (IRAD), 193 Intracardiac echocardiography (ICE), 290, 291, 292 Intracardiac shunts at atrial level as cause of dyspnea, 123–124 Intramural hematomas (IMHs), 192 and penetrating atherosclerotic ulcers (PAUs), imaging features, 197–198 Intravenous contrast, 222 Invasive coronary angiography (ICA), 24, 37 Inversion recovery (IR)-prepared gradient echo sequences, 212 Iron-overload cardiomyopathy, 277–279 Ischemic cascade, 140 Ischemic memory imaging, 64, 65–66, 83 Isoproterenol, 131 Jatene procedure, 247 Kawasaki’s disease, 240 Klippel-Trenaunay syndrome, 221 kt SENSE, 147 Kupio Ischemic Heart Disease (KIHD) risk factor study, 308 La Place, law of, 200 Late gadolinium enhancement (LGE) imaging, 50–51, 153, 266, 268, 270, 271, 273, 275 atrial fibrillation, 288, 289 clinical utility of, 152 using extracellular agents, 151 Le Compte maneuver, 246, 247 Left anterior descending (LAD) coronary artery, 5, 7, 13, 47, 63 Left atrial appendage (LAA), 285, 286, 287

Index

Left atrium (LA), 284. See also Atrial arrhythmias Left bundle branch block [LBBB], 45, 46, 47 Left circumflex (LCX) coronary arteries, 5 Left ventricular (LV) dilatation, 112, 113, 115, 116, 121 Left ventricular (LV) end-diastolic pressure (LVEDP), 176 Left ventricular (LV) function assessment with cardiac magnetic resonance (CMR), 75–76 Left ventricular (LV) inflow tract obstruction as cause of dyspnea, 119–120 Left ventricular (LV) remodeling, 52 Left ventricular (LV) systolic function and sudden cardiac death (SCD), 84 Left ventricular ejection fraction (LVEF), 6, 8, 9, 72, 84 Left ventricular hypertrophy (LVH), 115, 128 hypertension (HTN) and heart failure, 118 Left ventricular noncompaction (LVNC), 271–272 Left ventricular outflow tract (LVOT) obstruction, 131, 160 Leiomyosarcomas, 324 Leriche syndrome, 217 Leukemic infiltration, 327 Lipomas, 322 Lipomatous hypertrophy (LH), of interatrial septum, 330 Low-dose dobutamine echocardiography (LDDE), 49–50, 54, 79 Lower extremity arterial disease clinical presentation of, 209–210 MRA/CTA of, 210 pulse sequences in MRA, 211–212 Low-level exercise echocardiography (LLEE), 79 Lung/mediastinal tumors, 327 Lymphomas, 320, 326 M-mode echocardiography in valvular heart disease, 159–160 Magnetic resonance angiography (MRA) advantages and disadvantages of, 226 alternate imaging strategies, 214 artifacts and pitfalls, 221 clinical applications aneurysms and dissection, 219, 220 atherosclerotic PAD, 216–217 Buerger’s disease, 218 embolic disease, 218, 219 inflammatory arteritides, 219–221 postintervention evaluation, 217–219

339

noncontrast angiographic techniques, 215, 217 in peripheral arterial disease (PAD), 211–221 postprocessing and image interpretation, 215 protocol considerations contrast administration, 214 contrast timing, 213–214 field of view (FOV), 213 patient preparation and scan setup, 212–213 scanning, 213 pulse sequences in, of lower extremities 3D gradient echo angiographic sequences, 211–212 localization sequences, 211 postcontrast sequences, 212 time-resolved MRA, 211 restenosis assessment, 98 Magnetic resonance flow velocity measurements, 99 Magnetic resonance imaging (MRI). See also Cardiac magnetic resonance (CMR) imaging anatomical imaging techniques magnetic resonance angiography, 98 magnetic resonance flow velocity measurements, 99 aortic dissection, 204–205 for atherosclerosis, 310 functional imaging techniques, 94, 95, 96 myocardial perfusion, 143 clinical utility of, 146–147 first-pass gadolinium perfusion imaging, 144–145 future directions in, 147–148 quantification of perfusion, 145–146 Magnetic resonance pulmonary angiography (MRPA), 107–108 Magnevist, 144 Malignant cardiac masses benign conditions masquerading as tumors, 328 lipomatous hypertrophy (LH) of interatrial septum, 330 pericardial cysts, 330 postoperative inflammatory changes, 330, 331 thrombus, 328–330 lymphomas, 320, 326 metastatic disease, 320, 326–328 pericardial mesothelioma, 320, 326 sarcomas, 324 angiosarcomas, 320, 325 fibrosarcomas, 325 osteosarcomas, 320, 325 rhabdomyosarcomas, 325 Marfan syndrome, 122, 169

Mayo Clinic group, 32 Metabolic imaging [18F]2-deoxy,2-fluoroglucose (FDG) imaging with PET, 82–83 fatty acid imaging with BMIPP SPECT, 83–84 myocardial viability assessed with, 81–82 Metastatic disease, 320, 326–328 Microvascular disease, 32 Microvascular dysfunction, in hypertrophic cardiomyopathy, 271 Microvascular obstruction, 52 Mildly abnormal SPECT MPI, 27–28 Mitral annular calcification (MAC), 119, 161 Mitral regurgitation (MR), 112, 116, 117, 120, 121, 158, 162–163 cardiac computed tomography, 168 cardiac magnetic resonance imaging, 165–168 echocardiography, 163–165 etiologies of, 166 in hypertrophic cardiomyopathy (HCM), 131 severity of, 168 Mitral stenosis (MS) cardiac computed tomography, 162 cardiac magnetic resonance imaging, 161–162 dyspnea in, 120 echocardiography, 159–161 etiologies of, 159 severity of, 160 Mitral valve (MV), 119, 158 mitral regurgitation. See Mitral regurgitation (MR) mitral stenosis. See Mitral stenosis (MS) Multicenter postinfarction trial (MPIT), 74 Multidetector row computed tomography angiography (MDCT), 53, 67, 96–98, 168, 204, 266 Multi-Ethnic Study of Atherosclerosis (MESA) registry, 34 MultiHance, 144 Multiplanar reconstruction (MPR) images, 215 Multislice computed tomography (MSCT), 36, 173, 178, 266 Multivessel disease (MVD), 24, 25 Muscatine study, 308 Myocardial blood flow (MBF), 59 and myocardial uptake of nuclear tracers, 60 and wall thickening, 60 Myocardial contrast echocardiography (MCE), 49, 60, 62, 63, 64, 80, 81

Index

340

Myocardial fibrosis, 130 with hypertrophic cardiomyopathy (HCM), 133–134 Myocardial innervation, 84–85 Myocardial ischemia assessment, 78–79 CMR detection of regional wall motion abnormalities, 142 functional imaging techniques, 92–96 hibernation, myocardial, 139 inversion recovery sequence, 151–152 ischemia, 138–139 imaging, 140 MR myocardial perfusion, 143 clinical utility of, 146–147 first-pass gadolinium perfusion imaging, 144–145 future directions in, 147–148 quantification of perfusion, 145–146 nuclear cardiology myocardial perfusion SPECT, 141–142 PET perfusion imaging, 141 residual/potential, 84 stress ECG, 141–142 stunning, myocardial, 139 viability and hibernation, 138, 148 clinical utility of LGE, 152 CMR methods to, 151 comparison with other techniques to detecting, 152–153 late gadolinium enhancement (LGE), 151, 152 nuclear cardiology, 149–150 sequence design and improvements, 151–152 stress ECG, 150–151 Myocardial necrosis, 45 Myocardial perfusion imaging (MPI), 60–61, 74 in acute chest pain evaluation in emergency department (ED), 31–32 acute STEMI, 54–55 diagnostic impact, with SPECT and PET, 25–26 infarct size assessment, 75–76 myocardial salvage assessment, 75 Myocardial perfusion reserve index (MPRI), 146 Myocardial perfusion scintigraphy (MPS), 11 functional imaging techniques, 93, 94 hypertrophic cardiomyopathy (HCM), 132 noninvasive imaging techniques, 99–100 preoperative testing in noncardiac surgery, 231–232 with SPECT, 7, 140–141 Myocardial salvage assessment

with myocardial perfusion imaging (MPI), 75 Myocardial scar/tissue heterogeneity, 84 Myocardial tagging, 326 Myocardial viability assessment, 78–79 dobutamine stress echocardiography, 79–80 metabolic imaging [18F]2-deoxy,2-fluoroglucose (FDG) imaging with PET, 82–83 fatty acid imaging with BMIPP SPECT, 83–84 myocardial contrast echocardiography, 80, 81 SPECT MPI for Tc 99m perfusion tracers, 81–82 thallium, 81 Myocarditis, 274–275 Myosin-binding protein C (MYPBC3) gene, 133 MYPBC3, 133 Myxomas, 317, 318, 321–322 Myxomatous mitral regurgitation disease, 163 National Cancer Institute, 242 National Cholesterol Education Program (NCEP) ATP III guidelines, 299 Naxos syndrome, 267 Nephrogenic systemic fibrosis (NSF), 215 Neurofibromatosis, 221 New England Journal of Medicine, in 2007, 30 Niacin, 308 Nitric oxide, 311 Nitrogen 13-ammonia, 141 Noncalcified plaque, 305, 306 Noncardiac surgery. See also Preoperative risk stratification, in noncardiac surgery coronary revascularization prior to, 235–236 Noncontrast angiographic techniques, 215, 216 Nondilated DCM, 113 Nonhemorrhagic pleural, 200 Noninvasive atherosclerosis imaging brachial artery flow-mediated dilation, 310–311 carotid intima-media thickness (CIMT), 307 definition and measurement of, 307–308 role in risk assessment, 309–310 surrogate marker for atherosclerosis risk, 308–309 coronary artery calcium (CAC) scoring, 300 clinical application in asymptomatic patient, 302–304 and future challenges, 304, 305

prognostic value of, 302 rationale for risk assessment, 301 coronary multidetector computed tomography angiography, 305–307 Framingham risk score (FRS) application and limitations, 299–301 magnetic resonance imaging, 310 motivational effects of, 312 for risk stratification, 299–312 screening, rationale for, 299 Noninvasive coronary angiography, 61 Noninvasive imaging approaches acute coronary syndromes. See Acute coronary syndromes (ACSs) myocardial perfusion imaging, 60–61 noninvasive coronary angiography, 61 wall thickening assessment, 59–60 with unstable angina (UA)/non-ST elevation myocardial infarction (NSTEMI), 58–68 prognostic value of myocardial perfusion scintigraphy, 99 stress echocardiography, 99–100 exercise electrocardiography, 1–2 cardiac CT bypass grafts evaluation, 4–5 coronary artery calcium (CAC) scoring, 2 coronary artery stents evaluation, 4, 5 coronary CT angiography, 2–4, 5 stress echocardiography, 5–6 stress nuclear imaging, 6–11, 12 stress cardiac magnetic resonance imaging, 11–13 Nonischemic cardiomyopathy as cause of dyspnea, 115–117 Non-ST elevation myocardial infarction (NSTEMI)/unstable angina (UA). See Acute coronary syndromes (ACSs) Nonvalvular disease, 175 No-reflow zones, 49, 52 Normalcy rate, 24 North American Society for Cardiac Imaging, 67 Norwood Stage I procedure, 248 Nuclear cardiology myocardial perfusion SPECT, 140–141 PET perfusion imaging, 141 viability and hibernation, 150–151 Nuclear perfusion imaging, 6, 10–11, 12 Nuclear techniques diagnosis and management infarct avid imaging, 53–54 myocardial perfusion imaging, 54–55 risk stratification and prognosis, 55

Index

Omniscan, 144 Optimark, 144 Organic mitral regurgitation. See Primary mitral regurgitation Osteosarcomas, 320, 325 Oxygen consumption, 138, 241 Papillary fibroelastomas, 322, 323 Paragangliomas, 323 Parallel imaging (IPAT/SENSE/ ASSET), 211 Parenchymal lung disease as cause of dyspnea, 126 Parkes-Weber syndrome, 221 Patients, testing strategies selection in with known CAD, 17 without known CAD, 13 diabetes and renal dysfunction, 16–17 elderly, 16 special groups, 16–17 women, 16 Penetrating atherosclerotic ulcers (PAUs), 192 and intramural hematomas (IMHs), imaging features, 197–198 Percutaneous coronary intervention (PCI), 92, 71, 235 Percutaneous mitral balloon valvuloplasty (PMBV), 159, 161 Pericardial cysts, 330 Pericardial effusion, 200 as cause of dyspnea, 124 Pericardial mesothelioma, 320, 326 Perioperative ischemic evaluation (POISE) trial, 235 Peripheral arterial disease (PAD), 209 anatomic considerations distal vessels, 211 iliac and femoral arteries, 210 popliteal trifurcation, 210 CT angiography, 221–222 advantages and disadvantages of, 226 artifacts and pitfalls, 224 clinical applications, 223–224 protocol considerations, 222–223 duplex ultrasonography, 225 future developments, 225 imaging modality choice in, 225 lower extremity arterial disease, clinical presentation of, 209–210 magnetic resonance angiography, 211 advantages and disadvantages of, 226 alternate imaging strategies, 214 artifacts and pitfalls, 221 clinical applications, 216–221 noncontrast angiographic techniques, 215, 216 postprocessing and image interpretation, 215

3 41

protocol considerations, 212–214 pulse sequences in, 211–212 Phosphatidylserine, 63 Phosphocreatine-to-ATP ratio, 66 Phosphorus 31 spectra using nuclear magnetic resonance (31P-NMR) spectroscopy, 66 Physiologic tricuspid regurgitation, 178 Pleiotropic properties, 235 Pleural effusion as cause of dyspnea, 124 Polyarteritis nodosa, 223 Popliteal entrapment syndrome, 221 Popliteal trifurcation, 210 Positron emission tomography (PET), 1 [18F]2-deoxy,2-fluoroglucose (FDG) imaging with, 82–83 myocardial ischemia, 141 and SPECT, 6–10 MPI for CAD, 24–26 Postcontrast sequences, 212 Posterior tibial artery, 210, 211 Posteromedial papillary muscle, 48 Post-myocardial infarction (MI) complications, 47–48 prognosis, 50 Post-myocardial infarction (MI) risk stratification CAD burden, 78 cardiac imaging early after MI, 72–77 implantable cardiac defibrillators (ICD) benefit, 84 initial acute MI management contributes to, 71–72 LV systolic function, 84 myocardial innervation, 84–85 myocardial ischemia assessment, 78–79 myocardial scar/tissue heterogeneity, 84 myocardial viability assessment, 78–79 dobutamine stress echocardiography, 79–80 metabolic imaging with PET and SPECT, 82 myocardial contrast echocardiography, 80, 81 SPECT MPI for, 81–82 radionuclide imaging cardiac computed tomography, 77 cardiac magnetic resonance imaging, 75–77 gated equilibrium blood pool, 74 myocardial perfusion imaging (MPI), 74–75 residual myocardial ischemia, 84 revascularization, predicting benefit of, 78 sudden cardiac death (SCD), 84

transthoracic echocardiography, 73–74 Postoperative mediastinal and paracardiac inflammatory tissue, 330, 331 Preoperative risk stratification, in noncardiac surgery, 229–236 cardiac computed tomography, 232–233 cardiac magnetic resonance, 233–234 cardiac risk estimation, 229–230 cardioprotective medical therapy beta-blockers and statins, 234–235 clinical predictor of, 230 coronary revascularization prior to noncardiac surgery, 235–236 myocardial perfusion scintigraphy, 231–232 stress echocardiography, 230–231 Pressure half-time (PHT) method, 160, 176 Primary cardiomyopathies arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D), 267–268 dilated cardiomyopathy (DCM), 272–274 hypertrophic cardiomyopathy (HCM), 268–271 left ventricular noncompaction, 271–272 Primary mitral regurgitation, 163, 166 Primary tricuspid regurgitation, 178 ProHance, 144 Prospective Army Coronary Calcium Project, 301, 304, 305, 312 Proximal isovelocity surface area (PISA) method, 160 Pseudoaneurysms, 219, 225 Pseudostenosis, 224 Pulmonary embolism (PE) as cause of dyspnea, 124–125 clinical decision rules, 103–105 computed tomography pulmonary angiography (CTPA), 105–107 64-row detector CTPA protocol, 106 electrocardiography (ECG)-gated CTPA protocol, 106, 107 D-dimer tests, 104–105 diagnostic algorithms, 108–109 imaging techniques, 105–108 magnetic resonance pulmonary angiography (MRPA), 107–108 ventilation-perfusion (V-Q) scintigraphy, 105 Pulmonary vein (PV), 294 anatomy of, 289–290 and left atrium (LA), 288–289

Index

3 42

Pulmonic valve (PV), 182–183 cardiac computed tomography, 184 cardiac magnetic resonance imaging, 184 color and continuous-wave Doppler echocardiography, 184 echocardiography, 183–184 Quantification of aortic regurgitation, 177 of mitral regurgitation, 166 of perfusion, 145–146 of tricuspid regurgitation, 179 Radiofrequency ablation results, in pulmonary vein and left atrial wall, 294 Radionuclide imaging cardiac computed tomography, 77 cardiac magnetic resonance imaging in acute infarction, 76–77 infarct size assessment, 75–76 LV function assessment, 75 gated equilibrium blood pool, 74 myocardial perfusion imaging (MPI), 74–75 infarct size assessment, 75 myocardial salvage assessment, 75 Rastelli operation, 246 Real-time 3D echocardiography (RT3DE) for mitral valve, 160–161 for tricuspid valve, 180 Real-time cardiac imaging, 290 Referral bias, 24 Regional wall motion abnormalities CMR detection of, 142–143 Regurgitant fraction (RF) aortic regurgitation, 175 mitral regurgitation, 165, 167 Regurgitant volume (RV) aortic regurgitation, 175, 176 mitral regurgitation, 164, 166, 167, 168 tricuspid regurgitation, 181 Renal dysfunction and diabetes, 16–17 Residual myocardial ischemia, 84 Restenosis assessment anatomical imaging techniques, 96–99 Restrictive cardiomyopathy (RCM), 118–119. See also Constrictive pericarditis (CP) cardiac catheterization, 253–254 cardiovascular magnetic resonance, 257, 258 causes of, 252 clinical signs of, 253 echocardiography, 256–257 pathophysiology and presentation, 252–253 specific etiologies amyloidosis, 258–259

eosinophilic endomyocardial disease, 257–258 sarcoidosis, 259–260 storage diseases, 261 Revascularization, 14, 15. See also Coronary revascularization predicting benefit of, 78 Reversible ischemia, 45 Revised Cardiac Risk Index, 229, 230 Rhabdomyosarcomas, 325 Rheumatic fever, 158, 159 Rheumatic mitral stenosis, 120 Right coronary artery (RCA), 4, 330 Rime-of-flight (TOF) imaging, 215 Risk assessment with CAD event risk with abnormal scans, 27 after normal scan, 26, 27 incremental prognostic value, 26 mildly abnormal SPECT MPI, 27–28 moderate to severely abnormal SPECT MPI, 28 NSTEMI, 72 risk stratification principles, 26 risk thresholds, 26 using MPI for medical decision making, 28–29 using SPECT MPI in guiding decisions for catheterization and revascularization, 29–30 Risk stratification noninvasive atherosclerosis imaging for. See Noninvasive atherosclerosis imaging nuclear testing for, 26 of preoperative cardiac events in noncardiac surgery. See Preoperative risk stratification, in noncardiac surgery and prognosis CAD, 26 cardiac CT, 52, 53, 54 cardiac magnetic resonance, 51–52 echocardiography, 48–50 nuclear techniques, 55 Rubidium 82, 83, 142 Sarcoidosis guidelines for, 260 restrictive cardiomyopathy (RCM), 259–260 secondary cardiomyopathies, 276–277, 278 Sarcomas, 324 angiosarcomas, 320, 325 fibrosarcomas, 325 osteosarcomas, 320, 325 rhabdomyosarcomas, 325 Scan delay, 213 Scimitar syndrome, 239 Screening and asymptomatic HCM evaluation, role in, 132

Secondary cardiomyopathies amyloidosis, 275–276 Anderson-Fabry disease, 279–280 iron-overload cardiomyopathy, 277–279 sarcoidosis, 276–277, 278 Secondary mitral regurgitation, 163, 166 Secondary tricuspid regurgitation, 178 Segmental extent of hyperenhancement (SEH), 76 Semilunar valve stenosis as cause of dyspnea, 122–123 Semilunar valvular regurgitation as cause of dyspnea, 122 Senning and Mustard procedures, 246, 248 Septal myectomy for hypertrophic cardiomyopathy (HCM), 131, 132 Short tau inversion recovery (STIR), 265 Shunt flow, 240 Signal-to-noise ratio (SNR), 211 Simple congenital heart disease (CHD) aorta, coarctation of, 244–246 atrial septal defects (ASD), 242–244 defined, 238 Simpson’s rule, 287 Single photon emission computed tomography (SPECT), 1 noninvasive imaging diagnosis and prognosis in patients with suspected ACSs, 64–66 myocardial perfusion imaging (MPI) for myocardial viability assessment, 81–82 in specific patients with atypical clinical presentation, 32–33 and positron emission tomography (PET), 6–10 diagnostic testing accuracy of, MPI for CAD, 24–26 Sludge, 285, 286 Society of cardiovascular CT (SCCT), 36 South Bay Heart Watch study, 302 SPACETM sequence, 215 Speckle tracking, 263 Spontaneous echocontrast (SEC), 285 ST elevation myocardial infarctions (STEMI). See Acute ST elevation myocardial infarctions (STEMI) St Francis Heart Study, 34 Stanford classification, 196 Statins, cardioprotective effect of, 235 Steady-state free-precession (SSFP) sequences, 161, 171, 184, 205, 211 Stenoses, coronary, 138 Stents, endovascular, 218 Storage diseases, 261 Stress cardiac magnetic resonance imaging, 11–13 Stress ECG, 141–142 viability and hibernation, 150–151

Index

Stress echocardiography, 5–6 functional imaging techniques, 93–94, 95 noninvasive imaging, prognostic value of, 99–100 preoperative testing in noncardiac surgery, 230–231 Stress imaging approaches, 1–2, 14, 17 Stress nuclear imaging dual-modality CT and nuclear perfusion imaging, 10–11, 12 PET and SPECT, technical considerations for, 6–10 Stress-induced cardiomyopathy, 51 Stress-rest myocardial perfusion positron emission tomography (PET) scans, 10 Stunning, myocardial, 139 Subendocardial hypoenhancement, 52 Sudden cardiac death (SCD), 84 from arrhythmias, 267 in hypertrophic cardiomyopathy (HCM) patients, 127 Superficial femoral artery (SFA), 210, 217 Surgical septal myectomy for hypertrophic cardiomyopathy (HCM), 131, 132 Svensson classification, 196 Systolic anterior motion (SAM), 131 Systolic function evaluation with hypertrophic cardiomyopathy, 129 Systolic heart failure diagnosis of, 112–114 heart failure have normal ejection fraction (HFNEF), 112 T2-hyperintense regions, 51, 52 T2-weighted techniques, 51 Takatsubo cardiomyopathy, 51 Takayasu’s arteritis, 219 Task Force committee, 302–303 Tetralogy of Fallot, 174, 182, 183, 184, 239 Tetrofosmin, 60, 65, 140 Thallium myocardial perfusion imaging (MPI), 81 Third National Health and Nutrition Examination Survey, 299–300 Thromboangiitis obliterans. See Buerger’s disease Thromboembolic risk and atrial thrombi, 285–286 Thrombolysis in myocardial infarction (TIMI) risk index, 72 risk score, 62–63, 72 trial, 74 Thrombus, 59, 328–330

343

Tibioperoneal trunk, 210, 217 Time-resolved 3D gadolinium sequences, 241 Time-resolved imaging of contrast kinetics (TRICKS) MRA, 194, 211 Timing, contrast in multistation MRA, 213–214 Tissue characterization, 265 Tissue Doppler echocardiography (TDE), 259 Tissue Doppler imaging (TDI), 129, 263, 264 in atrial fibrillation, 284, 285, 288 Transesophageal echocardiography (TEE), 48, 49. See also Echocardiography 2D TEE of aortic valve, 170 mitral annular calcification on, 161, 162 of mitral valve, 159 3D TEE in mitral regurgitation, 165, 166 Transposition of the great arteries (TGA), 239, 246–248 Transseptal puncture, 290, 291 Transthoracic echocardiogram, 46, 47 Transthoracic echocardiography (TTE), 73–74, 316. See also Echocardiography in amyloidosis, 275–276 in Anderson-Fabry disease, 279 in aortic regurgitation, 176 in arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D), 268 in dilated cardiomyopathy, 273 in left ventricular noncompaction, 272 in mitral regurgitation, 163 in myocarditis, 274 in sarcoidosis, 277 Transthyretin, 258 Tricuspid regurgitation, 116, 121 Tricuspid valve (TV), 178 tricuspid regurgitation (TR), 178 cardiac computed tomography, 182 cardiac magnetic resonance imaging, 181–182 echocardiography, 178–181 tricuspid stenosis (TS), 178 Triphenyltetrazolium chloride (TTC), 50 True lumen, 192 and false lumina, 198–199 Truncation artifact. See Gibbs/truncation artifact Typical angina. See Chest pain Univentricular heart. See Functional single ventricles

Unstable angina (UA)/non-ST elevation myocardial infarction (NSTEMI). See Acute coronary syndromes (ACSs) US Food and Drug Administration (FDA), 64 Valsalva maneuver, 117, 131, 243 Valve Leaflets, 175 Valvular heart disease, 119 aortic valve. See Aortic regurgitation (AR); Aortic stenosis (AS) mitral valve. See Mitral regurgitation (MR); Mitral stenosis (MS) pulmonic valve. See Pulmonic valve (PV) tricuspid valve. See Tricuspid valve (TV) Vasculitis, 223 Vasodilator stress, 140, 145 Velocity time integral (VTI) aortic valve, 170 mitral valve, 160 Velocity-encoded MR (VENC) imaging, 167 Vena contracta (VC) aortic regurgitation, 175 mitral regurgitation, 164, 166, 168 Venous thromboembolism (VTE), 105 Ventilation-perfusion (V-Q) scintigraphy, 105 Ventricular aneurysm, 47, 48 Ventricular interdependence, 252, 254 Ventricular morphology assessment with hypertrophic cardiomyopathy, 127–128 Venturi theory, 131 Viability and hibernation, 148–149 nuclear cardiology, 149–150 stress ECG, 150–151 Volume coverage speed, 222 Volumetric interpolated breathhold examination (VIBE TM) imaging, 212 Wall thickening assessment, 59–60 Wall thickness and contractile reserve CMR to assess viability, 151 Wells rule, 103, 104 Wilkins score, 159 Williams syndrome, 221 Women, using exercise testing for diagnosing CAD in, 16 Wood, Paul, 158 X-linked lysosomal storage disorder, 261 Zwolle primary PCI index, 72